70 results on '"Miguel Mitne-Neto"'
Search Results
2. P075: Evaluation of PMS2 gene variant c.2182_2184delinsG by NGS in a Brazilian sample: How long-range PCR can solve homology?
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Daniele Paixão, Thalitta Hetamaro Ayala Lima, Larissa Souza Mario Bueno, Rafaela Rogério Floriano de Souza, Juliana Emilia Prior Carnavalli, Clarissa Gondim Picanço-Albuquerque, Isabelle Joyce de Lima Silva-Fernandes, Paulo Goberlânio de Barros Silva, Miguel Mitne-Neto, Wagner Antônio da Rosa Baratela, and Caroline Mônaco Moreira
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Genetics ,QH426-470 ,Medicine - Published
- 2023
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3. P434: Evaluation of monoallelic MUTYH variants in Brazilian patients: Potential selection bias
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Larissa Bueno, Daniele Paixão, Thalitta Lima, Juliana Carnavalli, Andrea Kiss, Caroline Moreira, Miguel Mitne-Neto, and Wagner Baratela
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Genetics ,QH426-470 ,Medicine - Published
- 2023
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- View/download PDF
4. P501: Pathogenic variants detected in high homology segments of the PMS2 gene in a Brazilian sample
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Thalitta Lima, Daniele Paixão, Larissa Bueno, Rafaela Sousa, Juliana Carnavalli, Maria Júlia Bezerra, Flavio Bitencourt, Maria Claudia Luciano, Rosane Sant'ana, Caroline Moreira, Wagner Baratela, and Miguel Mitne-Neto
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Genetics ,QH426-470 ,Medicine - Published
- 2023
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5. MHC Variants Associated With Symptomatic Versus Asymptomatic SARS-CoV-2 Infection in Highly Exposed Individuals
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Erick C. Castelli, Mateus V. de Castro, Michel S. Naslavsky, Marilia O. Scliar, Nayane S. B. Silva, Heloisa S. Andrade, Andreia S. Souza, Raphaela N. Pereira, Camila F. B. Castro, Celso T. Mendes-Junior, Diogo Meyer, Kelly Nunes, Larissa R. B. Matos, Monize V. R. Silva, Jaqueline Y. T. Wang, Joyce Esposito, Vivian R. Coria, Raul H. Bortolin, Mario H. Hirata, Jhosiene Y. Magawa, Edecio Cunha-Neto, Verônica Coelho, Keity S. Santos, Maria Lucia C. Marin, Jorge Kalil, Miguel Mitne-Neto, Rui M. B. Maciel, Maria Rita Passos-Bueno, and Mayana Zatz
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SARS-CoV-2 ,COVID-19 ,MHC ,HLA ,resistance ,asymptomatic ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Despite the high number of individuals infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who develop coronavirus disease 2019 (COVID-19) symptoms worldwide, many exposed individuals remain asymptomatic and/or uninfected and seronegative. This could be explained by a combination of environmental (exposure), immunological (previous infection), epigenetic, and genetic factors. Aiming to identify genetic factors involved in immune response in symptomatic COVID-19 as compared to asymptomatic exposed individuals, we analyzed 83 Brazilian couples where one individual was infected and symptomatic while the partner remained asymptomatic and serum-negative for at least 6 months despite sharing the same bedroom during the infection. We refer to these as “discordant couples”. We performed whole-exome sequencing followed by a state-of-the-art method to call genotypes and haplotypes across the highly polymorphic major histocompatibility complex (MHC) region. The discordant partners had comparable ages and genetic ancestry, but women were overrepresented (65%) in the asymptomatic group. In the antigen-presentation pathway, we observed an association between HLA-DRB1 alleles encoding Lys at residue 71 (mostly DRB1*03:01 and DRB1*04:01) and DOB*01:02 with symptomatic infections and HLA-A alleles encoding 144Q/151R with asymptomatic seronegative women. Among the genes related to immune modulation, we detected variants in MICA and MICB associated with symptomatic infections. These variants are related to higher expression of soluble MICA and low expression of MICB. Thus, quantitative differences in these molecules that modulate natural killer (NK) activity could contribute to susceptibility to COVID-19 by downregulating NK cell cytotoxic activity in infected individuals but not in the asymptomatic partners.
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- 2021
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6. Exome sequencing and targeted gene panels: a simulated comparison of diagnostic yield using data from 158 patients with rare diseases
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Caio Robledo D’Angioli Costa Quaio, María José Rivadeneira Obando, Sandro Felix Perazzio, Aurelio Pimenta Dutra, Christine Hsiaoyun Chung, Caroline Monaco Moreira, Gil Monteiro Novo Filho, Patricia Rossi Sacramento-Bobotis, Michele Groenner Penna, Rafaela Rogerio Floriano de Souza, Vivian Pedigone Cintra, Juliana Emilia Prior Carnavalli, Rafael Alves da Silva, Monize Nakamoto Provisor Santos, Daniele Paixão, Wagner Antonio da Rosa Baratela, Caroline Olivati, Gustavo Marquezani Spolador, Maria Carolina Pintao, Alexandre Ricardo dos Santos Fornari, Matheus Burger, Rodrigo Fernandes Ramalho, Otavio Jose Eulalio Pereira, Elisa Napolitano e Ferreira, Miguel Mitne-Neto, and Chong Ae Kim
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Exome sequencing ,Next-generation sequencing ,targeted gene panels ,diagnostic yield ,NGS panel ,Genetics ,QH426-470 - Abstract
Abstract Next-generation sequencing (NGS) has altered clinical genetic testing by widening the access to molecular diagnosis of genetically determined rare diseases. However, physicians may face difficulties selecting the best diagnostic approach. Our goal is to estimate the rate of possible molecular diagnoses missed by different targeted gene panels using data from a cohort of patients with rare genetic diseases diagnosed with exome sequencing (ES). For this purpose, we simulated a comparison between different targeted gene panels and ES: the list of genes harboring clinically relevant variants from 158 patients was used to estimate the theoretical rate of diagnoses missed by NGS panels from 53 different NGS panels from eight different laboratories. Panels presented a mean rate of missed diagnoses of 64% (range 14%-100%) compared to ES, representing an average predicted sensitivity of 36%. Metabolic abnormalities represented the group with highest mean of missed diagnoses (86%), while seizure represented the group with lowest mean (46%). Focused gene panels are restricted in covering select sets of genes implicated in specific diseases and they may miss molecular diagnoses of rare diseases compared to ES. However, their role in genetic diagnosis remains important especially for well-known genetic diseases with established genetic locus heterogeneity.
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- 2021
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7. A Novel Saliva RT-LAMP Workflow for Rapid Identification of COVID-19 Cases and Restraining Viral Spread
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Gerson Shigeru Kobayashi, Luciano Abreu Brito, Danielle de Paula Moreira, Angela May Suzuki, Gabriella Shih Ping Hsia, Lylyan Fragoso Pimentel, Ana Paula Barreto de Paiva, Carolina Regoli Dias, Naila Cristina Vilaça Lourenço, Beatriz Araujo Oliveira, Erika Regina Manuli, Marcelo Andreetta Corral, Natale Cavaçana, Miguel Mitne-Neto, Maria Mirtes Sales, Luiz Phellipe Dell’ Aquila, Alvaro Razuk Filho, Eduardo Fagundes Parrillo, Maria Cássia Mendes-Corrêa, Ester Cerdeira Sabino, Silvia Figueiredo Costa, Fabio Eudes Leal, Germán Gustavo Sgro, Chuck Shaker Farah, Mayana Zatz, and Maria Rita Passos-Bueno
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LAMP (loop-mediated isothermal amplification) assay ,2019 novel coronavirus ,saliva ,viral diagnostics ,Medicine (General) ,R5-920 - Abstract
Rapid diagnostics is pivotal to curb SARS-CoV-2 transmission, and saliva has emerged as a practical alternative to naso/oropharyngeal (NOP) specimens. We aimed to develop a direct RT-LAMP (reverse transcription loop-mediated isothermal amplification) workflow for viral detection in saliva, and to provide more information regarding its potential in curbing COVID-19 transmission. Clinical and contrived specimens were used to optimize formulations and sample processing protocols. Salivary viral load was determined in symptomatic patients to evaluate the clinical performance of the test and to characterize saliva based on age, gender and time from onset of symptoms. Our workflow achieved an overall sensitivity of 77.2% (n = 90), with 93.2% sensitivity, 97% specificity, and 0.895 Kappa for specimens containing >102 copies/μL (n = 77). Further analyses in saliva showed that viral load peaks in the first days of symptoms and decreases afterwards, and that viral load is ~10 times lower in females compared to males, and declines following symptom onset. NOP RT-PCR data did not yield relevant associations. This work suggests that saliva reflects the transmission dynamics better than NOP specimens, and reveals gender differences that may reflect higher transmission by males. This saliva RT-LAMP workflow can be applied to track viral spread and, to maximize detection, testing should be performed immediately after symptoms are presented, especially in females.
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- 2021
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8. Development and validation of a variant detection workflow for BRCA1 and BRCA2 genes and its clinical application based on the Ion Torrent technology
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Ana Lígia Buzolin, Caroline Mônaco Moreira, Patricia Rossi Sacramento, Andre Yuji Oku, Alexandre Ricardo dos Santos Fornari, David Santos Marco Antonio, Caio Robledo D Angioli Costa Quaio, Wagner Rosa Baratela, and Miguel Mitne-Neto
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Cancer ,Breast ,Ovarian ,Ion Torrent ,BRCA ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background Breast cancer is the most common among women worldwide, and ovarian cancer is the most difficult gynecological tumor to diagnose and with the lowest chance of cure. Mutations in BRCA1 and BRCA2 genes increase the risk of ovarian cancer by 60% and breast cancer by up to 80% in women. Molecular tests allow a better orientation for patients carrying these mutations, affecting prophylaxis, treatment, and genetic counseling. Results Here, we evaluated the performance of a panel for BRCA1 and BRCA2, using the Ion Torrent PGM (Life Technologies) platform in a customized workflow and multiplex ligation-dependent probe amplification for detection of mutations, insertions, and deletions in these genes. We validated the panel with 26 samples previously analyzed by Myriad Genetics Laboratory, and our workflow showed 95.6% sensitivity and 100% agreement with Myriad reports, with 85% sensitivity on the positive control sample from NIST. We also screened 68 clinical samples and found 22 distinct mutations. Conclusions The selection of a robust methodology for sample preparation and sequencing, together with bioinformatics tools optimized for the data analysis, enabled the development of a very sensitive test with high reproducibility. We also highlight the need to explore the limitations of the NGS technique and the strategies to overcome them in a clinically confident manner.
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- 2017
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9. JAK2-mutated acute myeloid leukemia: comparison of next-generation sequencing (NGS) and single nucleotide polymorphism array (SNPa) findings between two cases
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Thiago Rodrigo de Noronha, Miguel Mitne-Neto, and Maria de Lourdes Chauffaille
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Cytogenetics ,Leukemia ,Myeloid ,Acute ,Polymorphism ,Single Nucleotide ,Medicine ,Internal medicine ,RC31-1245 - Abstract
JAK2 mutations are rare in de novo acute myeloid leukemia (AML), and JAK2-mutated acute myeloid leukemia (AML) patients usually have a previous history of myeloproliferative neoplasms (MPNs). Current advances in laboratory techniques, such as single nucleotide polymorphism array (SNPa) and next-generation sequencing (NGS), have facilitated new insight into the molecular basis of hematologic diseases. Herein, we present two cases of JAK2-mutated AML in which both SNPa and NGS methods added valuable information. Both cases had leukemogenic collaboration, namely, copy-neutral loss of heterozygosity (CN-LOH), detected on chromosome 9. One of the cases exhibited both JAK2 and IDH2 mutations, most likely having originated as an MPN with leukemic transformation, while the other case was classified as a de novo AML with JAK2, CEBPA, and FLT3 mutations.
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- 2019
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10. Small-fibre Neuropathy in Patients with Familial Amyotrophic Lateral Sclerosis Type 8
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Marcela Câmara Machado-Costa, Miguel Mitne-Neto, Luiza Helena Degani Costa, Luciana Moura Alves, Acary Souza Bulle Oliveira, Mayana Zatz, and Helga Cristina Almeida Silva
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Neurology ,Neurology (clinical) ,General Medicine - Abstract
Background: Amyotrophic lateral sclerosis (ALS) is a degenerative disease of the nervous system that primarily affects motor neurons. ALS type 8 (ALS8) is a familiar form with predominant involvement of lower motor neurons, tremor, and slow progression. Objective: The aim of this study was to describe sensory involvement in a cohort of ALS8 patients and compare it with the characteristics of sporadic ALS (sALS) patients and controls. Methods: We compared data from 40 ALS8 and 10 sALS patients assessed by neurological evaluation and electrophysiological study. Skin biopsies were performed in these patients and 12 controls for analysis of intraepidermal nerve fiber (IENF) density by protein gene product 9.5 (PGP 9.5) immunohistochemistry. Results: The ALS8 group was younger than the sALS group at the onset of symptoms (p < 0.05) and had a longer disease evolution (p < 0.01). Sensory abnormalities were evident in 35% of the ALS8 and 30% of the sALS patients by neurological examination, and all ALS patients presented normal sensory nerve action potentials. Despite being similar in the ALS8 and sALS groups, IENF density in the ALS8 group was lower than that in the controls (p < 0.0005). In the ALS8 group, IENF density was significantly lower in patients with impairment of vibratory sensation than in those without this finding (p < 0.05) and in females than in males (p < 0.05). Conclusion: Sensory impairment and decreased IENF density are present in ALS8 patients at a frequency and intensity similar to that in the sALS group.
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- 2022
11. Frequency of carriers for rare recessive Mendelian diseases in a Brazilian cohort of 320 patients
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Matheus Carvalho Bürger, Patricia Rossi Sacramento-Bobotis, Sandro Félix Perazzio, Monize Nakamoto Provisor Santos, Rafaela Rogerio Floriano de Souza, Vivian Pedigone Cintra, Chong Ae Kim, Gustavo Marquezani Spolador, Michele Groenner Penna, Miguel Mitne-Neto, Maria Carolina Pintao, Rodrigo Fernandes Ramalho, Gil Monteiro Novo Filho, Wagner A.R. Baratela, Christine Hsiaoyun Chung, Caroline Monaco Moreira, Otavio Jose Eulalio Pereira, Aurelio Pimenta Dutra, Alexandre Ricardo dos Santos Fornari, Rafael Alves da Silva, Daniele Paixão, Caroline Olivati, Caio Robledo D'Angioli Costa Quaio, Elisa Napolitano Ferreira, and Juliana Emilia Prior Carnavalli
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Pediatrics ,medicine.medical_specialty ,business.industry ,Hearing loss ,Disease ,medicine.disease ,Cohort Studies ,Epilepsy ,symbols.namesake ,Rare Diseases ,Intellectual Disability ,Exome Sequencing ,Cohort ,Epidemiology ,Genetics ,Mendelian inheritance ,symbols ,Humans ,Medicine ,medicine.symptom ,business ,Mendelian disorders ,Brazil ,Genetics (clinical) ,Exome sequencing - Abstract
Several Mendelian disorders follow an autosomal recessive inheritance pattern. Epidemiological information on many inherited disorders may be useful to guide health policies for rare diseases, but it is often inadequate, particularly in developing countries. We aimed to calculate the carrier frequencies of rare autosomal recessive Mendelian diseases in a cohort of Brazilian patients using whole exome sequencing (WES). We reviewed the molecular findings of WES from 320 symptomatic patients who had carrier status for recessive diseases. Using the Hardy-Weinberg equation, we estimated recessive disease frequencies (q2 ) considering the respective carrier frequencies (2pq) observed in our study. We calculated the sensitivity of carrier screening tests based on lists of genes from five different clinical laboratories that offer them in Brazil. A total of 425 occurrences of 351 rare variants were reported in 278 different genes from 230 patients (71.9%). Almost half (48.8%) were carriers of at least one heterozygous pathogenic/likely pathogenic variant for rare metabolic disorders, while 25.9% of epilepsy, 18.1% of intellectual disabilities, 15.6% of skeletal disorders, 10.9% immune disorders, and 9.1% of hearing loss. We estimated that an average of 67% of the variants would not have been detected by carrier screening panels. The combined frequencies of autosomal recessive diseases were estimated to be 26.39/10,000 (or ~0.26%). This study shows the potential research utility of WES to determine carrier status, which may be a possible strategy to evaluate the clinical and social burden of recessive diseases at the population level and guide the optimization of carrier screening panels.
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- 2021
12. Recurrence of COVID-19 associated with reduced T-cell responses in a monozygotic twin pair
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Mateus V. de Castro, Keity S. Santos, Juliana S. Apostolico, Edgar R. Fernandes, Rafael R. Almeida, Gabriel Levin, Jhosiene Y. Magawa, João Paulo S. Nunes, Mirian Bruni, Marcio M. Yamamoto, Ariane C. Lima, Monize V. R. Silva, Larissa R. B. Matos, Vivian R. Coria, Erick C. Castelli, Marilia O. Scliar, Andreia Kuramoto, Fernanda R. Bruno, Lucas C. Jacintho, Kelly Nunes, Jaqueline Y. T. Wang, Veronica P. Coelho, Miguel Mitne Neto, Rui M. B. Maciel, Michel S. Naslavsky, Maria Rita Passos-Bueno, Silvia B. Boscardin, Daniela S. Rosa, Jorge Kalil, Mayana Zatz, Edecio Cunha-Neto, Universidade de São Paulo (USP), Instituto Nacional de Ciência e Tecnologia - Iii-INCT, Universidade Federal de São Paulo (UNIFESP), Universidade Estadual Paulista (UNESP), and Fleury Laboratory
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Adult ,Male ,Immunity, Cellular ,recurrence ,Adolescent ,SARS-CoV-2 ,QH301-705.5 ,T-Lymphocytes ,Research ,severe acute respiratory distress syndrome coronavirus 2 ,General Neuroscience ,Immunology ,Epitopes, T-Lymphocyte ,COVID-19 ,T cell ,Twins, Monozygotic ,twins ,immunity ,General Biochemistry, Genetics and Molecular Biology ,Humans ,Female ,Biology (General) ,IMUNOGENÉTICA ,Research Articles - Abstract
Made available in DSpace on 2022-04-29T08:46:34Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-01-01 Recurrence of COVID-19 in recovered patients has been increasingly reported. However, the immune mechanisms behind the recurrence have not been thoroughly investigated. The presence of neutralizing antibodies (nAbs) in recurrence/reinfection cases suggests that other types of immune response are involved in protection against recurrence. Here, we investigated the innate type I/III interferon (IFN) response, binding and nAb assays and T-cell responses to severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) with IFN gamma (IFNγ) enzyme-linked spot assay (ELISPOT) in three pairs of young adult monozygotic (MZ) twins with previous confirmed COVID-19, one of them presenting a severe recurrence four months after the initial infection. Twin studies have been of paramount importance to comprehend the immunogenetics of infectious diseases. Each MZ twin pair was previously exposed to SARS-CoV-2, as seen by clinical reports. The six individuals presented similar overall recovered immune responses except for the recurrence case, who presented a drastically reduced number of recognized SARS-CoV-2 T-cell epitopes on ELISPOT as compared to her twin sister and the other twin pairs. Our results suggest that the lack of a broad T-cell response to initial infection may have led to recurrence, emphasizing that an effective SARS-CoV-2-specific T-cell immune response is key for complete viral control and avoidance of clinical recurrence of COVID-19. Human Genome and Stem Cell Research Center (HUG-CELL) Biosciences Institute Universidade de São Paulo, SP Laboratory of Immunology Heart Institute (InCor) Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), SP Institute for Investigation in Immunology Instituto Nacional de Ciência e Tecnologia - Iii-INCT, SP Division of Clinical Immunology and Allergy Department of Medicine Faculdade de Medicina da Universidade de São Paulo (FMUSP), SP Department of Microbiology Immunology and Parasitology Universidade Federal de São Paulo (UNIFESP/EPM), SP Department of Parasitology Biosciences Institute Universidade de São Paulo, SP School of Medicine Universidade Estadual Paulista (UNESP), SP Fleury Laboratory, SP School of Medicine Universidade Estadual Paulista (UNESP), SP
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- 2022
13. Different gene expression profiles in iPSC-derived motor neurons from ALS8 patients with variable clinical courses suggest mitigating pathways for neurodegeneration
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Danyllo Oliveira, Livia Luz, Felipe de Souza Leite, Carolini Kaid, Oswaldo Keith Okamoto, Mayana Zatz, Uirá Souto Melo, Thalita Figueiredo, Luiz Carlos de Caires, Andréa L. Sertié, Sergio Verjovski-Almeida, Ernesto Goulart, Murilo S. Amaral, David A. Morales-Vicente, Miguel Mitne-Neto, Claudia D. C. Navarro, Joyce Esposito, and Luciana M Alves
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Male ,Induced Pluripotent Stem Cells ,Vesicular Transport Proteins ,Biology ,Endoplasmic Reticulum ,03 medical and health sciences ,0302 clinical medicine ,Gene expression ,Genetics ,medicine ,Humans ,RNA-Seq ,Amyotrophic lateral sclerosis ,Molecular Biology ,Gene ,Genetics (clinical) ,Aged ,030304 developmental biology ,Motor Neurons ,0303 health sciences ,Amyotrophic Lateral Sclerosis ,Neurodegeneration ,Cell Differentiation ,General Medicine ,Middle Aged ,Motor neuron ,VAPB ,medicine.disease ,Mitochondria ,Cell biology ,Gene expression profiling ,Oxidative Stress ,Proteostasis ,medicine.anatomical_structure ,Gene Expression Regulation ,Nerve Degeneration ,Female ,030217 neurology & neurosurgery - Abstract
Amyotrophic lateral sclerosis type 8 (ALS8) is an autosomal dominant form of ALS, which is caused by pathogenic variants in the VAPB gene. Here we investigated five ALS8 patients, classified as ‘severe’ and ‘mild’ from a gigantic Brazilian kindred, carrying the same VAPB mutation but displaying different clinical courses. Copy number variation and whole exome sequencing analyses in such individuals ruled out previously described genetic modifiers of pathogenicity. After deriving induced pluripotent stem cells (iPSCs) for each patient (N = 5) and controls (N = 3), motor neurons were differentiated, and high-throughput RNA-Seq gene expression measurements were performed. Functional cell death and oxidative metabolism assays were also carried out in patients’ iPSC-derived motor neurons. The degree of cell death and mitochondrial oxidative metabolism were similar in iPSC-derived motor neurons from mild patients and controls and were distinct from those of severe patients. Similar findings were obtained when RNA-Seq from such cells was performed. Overall, 43 genes were upregulated and 66 downregulated in the two mild ALS8 patients when compared with severe ALS8 individuals and controls. Interestingly, significantly enriched pathways found among differentially expressed genes, such as protein translation and protein targeting to the endoplasmic reticulum (ER), are known to be associated with neurodegenerative processes. Taken together, the mitigating mechanisms here presented appear to maintain motor neuron survival by keeping translational activity and protein targeting to the ER in such cells. As ALS8 physiopathology has been associated with proteostasis mechanisms in ER–mitochondria contact sites, such differentially expressed genes appear to relate to the bypass of VAPB deficiency.
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- 2020
14. Author response for 'Recurrence of COVID-19 associated with reduced T-cell responses in a monozygotic twin pair'
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null Mateus V. de Castro, null Keity S. Santos, null Juliana S. Apostolico, null Edgar R. Fernandes, null Rafael R. Almeida, null Gabriel Levin, null Jhosiene Y. Magawa, null João Paulo S. Nunes, null Mirian Bruni, null Marcio M. Yamamoto, null Ariane C. Lima, null Monize V. R. Silva, null Larissa R. B. Matos, null Vivian R. Coria, null Erick C. Castelli, null Marilia O. Scliar, null Andreia Kuramoto, null Fernanda R. Bruno, null Lucas C. Jacintho, null Kelly Nunes, null Jaqueline Y. T. Wang, null Veronica P. Coelho, null Miguel Mitne Neto, null Rui M. B. Maciel, null Michel S. Naslavsky, null Maria Rita Passos-Bueno, null Silvia B. Boscardin, null Daniela S. Rosa, null Jorge Kalil, null Mayana Zatz, and null Edecio Cunha-Neto
- Published
- 2021
15. Genetic risk factors and Covid-19 severity in Brazil: results from BRACOVID Study
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José Osmar Medina Pestana, Taniela M Bes, Miguel Mitne-Neto, Silvia Figueiredo Costa, Carla M Dinardo, Alexandre C. Pereira, Cinthia E. Jannes, José Eduardo Krieger, Mariliza Velho, Alberto José da Silva Duarte, Karina Ramos Valino, Emanuelle Marques, and Alexandre R Santos
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Disease surveillance ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Pandemic ,Haplotype ,Locus (genetics) ,Genome-wide association study ,Disease ,Biology ,Demography - Abstract
The Covid-19 pandemic has changed the paradigms for disease surveillance and rapid deployment of scientific-based evidence for understanding disease biology, susceptibility, and treatment. We have organized a large-scale genome-wide association study in Sars-Cov-2 infected individuals in Sao Paulo, Brazil, one of the most affected areas of the pandemic in the country, itself one of the most affected in the world. Here we present the results of the initial analysis in the first 5,233 participants of the BRACOVID study.We have conducted a GWAS for Covid-19 hospitalization enrolling 3533 cases (hospitalized Covid-19 participants) and 1700 controls (non-hospitalized Covid-19 participants). Models were adjusted by age, sex and the 4 first principal components. A meta-analysis was also conducted merging BRACOVID hospitalization data with the Human Genetic Initiative (HGI) Consortia results.BRACOVID results validated most loci previously identified in the HGI meta-analysis. In addition, no significant heterogeneity according to ancestral group within the Brazilian population was observed for the two most important Covid-19 severity associated loci: 3p21.31 and Chr21 near IFNAR2. Using only data provided by BRACOVID a new genome-wide significant locus was identified on Chr1 near the genes DSTYK and RBBP5. The associated haplotype has also been previously associated with a number of blood cell related traits and might play a role in modulating the immune response in Covid-19 cases.
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- 2021
16. Genetic risk factors and COVID-19 severity in Brazil: results from BRACOVID study
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Alexandre C Pereira, Taniela M Bes, Mariliza Velho, Emanuelle Marques, Cintia E Jannes, Karina R Valino, Carla L Dinardo, Silvia F Costa, Alberto J S Duarte, Alexandre R Santos, Miguel Mitne-Neto, Jose Medina-Pestana, and Jose E Krieger
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Risk Factors ,SARS-CoV-2 ,Receptor-Interacting Protein Serine-Threonine Kinases ,Genetics ,COVID-19 ,Humans ,General Medicine ,Molecular Biology ,Genetics (clinical) ,Brazil ,Genome-Wide Association Study - Abstract
The coronavirus disease 2019 (COVID-19) pandemic has changed the paradigms for disease surveillance and rapid deployment of scientific-based evidence for understanding disease biology, susceptibility and treatment. We have organized a large-scale genome-wide association study (GWAS) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected individuals in Sao Paulo, Brazil, one of the most affected areas of the pandemic in the country, itself one of the most affected in the world. Here, we present the results of the initial analysis in the first 5233 participants of the BRACOVID study. We have conducted a GWAS for COVID-19 hospitalization enrolling 3533 cases (hospitalized COVID-19 participants) and 1700 controls (non-hospitalized COVID-19 participants). Models were adjusted by age, sex and the 4 first principal components. A meta-analysis was also conducted merging BRACOVID hospitalization data with the Human Genetic Initiative (HGI) Consortia results. BRACOVID results validated most loci previously identified in the HGI meta-analysis. In addition, no significant heterogeneity according to ancestral group within the Brazilian population was observed for the two most important COVID-19 severity associated loci: 3p21.31 and Chr21 near IFNAR2. Using only data provided by BRACOVID, a new genome-wide significant locus was identified on Chr1 near the genes DSTYK and RBBP5. The associated haplotype has also been previously associated with a number of blood cell related traits and might play a role in modulating the immune response in COVID-19 cases.
- Published
- 2021
17. Exome sequencing and targeted gene panels: a simulated comparison of diagnostic yield using data from 158 patients with rare diseases
- Author
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Gil Monteiro Novo Filho, Maria Carolina Pintao, Caroline Monaco Moreira, Otavio Jose Eulalio Pereira, Caroline Olivati, Caio Robledo D'Angioli Costa Quaio, Juliana Emilia Prior Carnavalli, María José Rivadeneira Obando, Patricia Rossi Sacramento-Bobotis, Chong Ae Kim, Aurelio Pimenta Dutra, Rodrigo Fernandes Ramalho, Elisa Napolitano Ferreira, Matheus Carvalho Bürger, Miguel Mitne-Neto, Vivian Pedigone Cintra, Sandro Félix Perazzio, Gustavo Marquezani Spolador, Christine Hsiaoyun Chung, Rafael Alves da Silva, Monize Nakamoto Provisor Santos, Rafaela Rogerio Floriano de Souza, Michele Groenner Penna, Wagner A.R. Baratela, Alexandre Ricardo dos Santos Fornari, and Daniele Paixão
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Exome sequencing ,Biology ,QH426-470 ,targeted gene panels ,Bioinformatics ,NGS panel ,DNA sequencing ,Gene panel ,diagnostic yield ,Cohort ,Human and Medical Genetics ,Clinical genetic ,Genetics ,Next-generation sequencing ,Medical diagnosis ,Genetic diagnosis ,Molecular Biology ,Gene - Abstract
Next-generation sequencing (NGS) has altered clinical genetic testing by widening the access to molecular diagnosis of genetically determined rare diseases. However, physicians may face difficulties selecting the best diagnostic approach. Our goal is to estimate the rate of possible molecular diagnoses missed by different targeted gene panels using data from a cohort of patients with rare genetic diseases diagnosed with exome sequencing (ES). For this purpose, we simulated a comparison between different targeted gene panels and ES: the list of genes harboring clinically relevant variants from 158 patients was used to estimate the theoretical rate of diagnoses missed by NGS panels from 53 different NGS panels from eight different laboratories. Panels presented a mean rate of missed diagnoses of 64% (range 14%-100%) compared to ES, representing an average predicted sensitivity of 36%. Metabolic abnormalities represented the group with highest mean of missed diagnoses (86%), while seizure represented the group with lowest mean (46%). Focused gene panels are restricted in covering select sets of genes implicated in specific diseases and they may miss molecular diagnoses of rare diseases compared to ES. However, their role in genetic diagnosis remains important especially for well-known genetic diseases with established genetic locus heterogeneity.
- Published
- 2021
18. Genome-wide identification of the genetic basis of amyotrophic lateral sclerosis
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Sai Zhang, Johnathan Cooper-Knock, Annika K. Weimer, Minyi Shi, Tobias Moll, Jack N.G. Marshall, Calum Harvey, Helia Ghahremani Nezhad, John Franklin, Cleide dos Santos Souza, Ke Ning, Cheng Wang, Jingjing Li, Allison A. Dilliott, Sali Farhan, Eran Elhaik, Iris Pasniceanu, Matthew R. Livesey, Chen Eitan, Eran Hornstein, Kevin P. Kenna, Jan H. Veldink, Laura Ferraiuolo, Pamela J. Shaw, Michael P. Snyder, Ian Blair, Naomi R. Wray, Matthew Kiernan, Miguel Mitne Neto, Adriano Chio, Ruben Cauchi, Wim Robberecht, Philip van Damme, Philippe Corcia, Philippe Couratier, Orla Hardiman, Russell McLaughin, Marc Gotkine, Vivian Drory, Nicola Ticozzi, Vincenzo Silani, Leonard H. van den Berg, Mamede de Carvalho, Jesus S. Mora Pardina, Monica Povedano, Peter Andersen, Markus Weber, Nazli A. Başak, Ammar Al-Chalabi, Chris Shaw, Karen E. Morrison, John E. Landers, Jonathan D. Glass, and Project MinE ALS Sequencing Consortium
- Subjects
Motor Neurons ,Cell Death ,General Neuroscience ,Amyotrophic Lateral Sclerosis ,Induced Pluripotent Stem Cells ,Cytoskeletal Proteins ,Amyotrophic lateral sclerosis -- Diagnosis ,Genes ,Machine learning ,Genetics ,Humans ,Epigenetics ,Nervous system -- Degeneration ,Adaptor Proteins, Signal Transducing ,Genome-Wide Association Study - Abstract
Amyotrophic lateral sclerosis (ALS) is a complex disease that leads to motor neuron death. Despite heritability estimates of 52%, genome-wide association studies (GWASs) have discovered relatively few loci. We developed a machine learning approach called RefMap, which integrates functional genomics with GWAS summary statistics for gene discovery. With transcriptomic and epigenetic profiling of motor neurons derived from induced pluripotent stem cells (iPSCs), RefMap identified 690 ALS-associated genes that represent a 5-fold increase in recovered heritability. Extensive conservation, transcriptome, network, and rare variant analyses demonstrated the functional significance of candidate genes in healthy and diseased motor neurons and brain tissues. Genetic convergence between common and rare variation highlighted KANK1 as a new ALS gene. Reproducing KANK1 patient mutations in human neurons led to neurotoxicity and demonstrated that TDP-43 mislocalization, a hallmark pathology of ALS, is downstream of axonal dysfunction. RefMap can be readily applied to other complex diseases., peer-reviewed
- Published
- 2021
19. Genética e Esclerose Lateral Amiotrófica
- Author
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Miguel Mitne Neto
- Subjects
Neurology ,Neurology (clinical) - Published
- 2019
20. Additional information offered by single nucleotide polymorphism array advantages in two myelodysplastic syndromes with excess blasts cases and future perspectives
- Author
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Miguel Mitne-Neto, Maria de Lourdes Lopes Ferrari Chauffaille, and Thiago Rodrigo de Noronha
- Subjects
business.industry ,Myelodysplastic syndromes ,Single Nucleotide Polymorphism Array ,medicine ,Immunology and Allergy ,Case Report ,Hematology ,Computational biology ,medicine.disease ,business - Published
- 2018
21. 'Immunogenetics of resistance to SARS-CoV-2 infection in discordant couples'
- Author
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Vivian R. Coria, Mayana Zatz, Mateus V. de Castro, Jaqueline T. W. Wang, Erick C. Castelli, Jorge Kalil, Raphaela Neto Pereira, Marilia O. Scliar, Larissa R. B. Matos, Maria Lucia C. Marin, Keity Souza Santos, Maria Rita Passos-Bueno, Verônica Coelho, Michel S Naslavsky, Kelly Nunes, Mario Hiroyuki Hirata, Heloisa S. Andrade, Diogo Meyer, Nayane S. B. Silva, Miguel Mitne Neto, Celso T. Mendes-Junior, Monize V. R. Silva, Andreia S. Souza, Camila Ferreira Bannwart Castro, Joyce Esposito, Rui M. B. Maciel, Edecio Cunha-Neto, Raul Hernandes Bortolin, and Jhosiene Y. Magawa
- Subjects
biology ,INFECÇÕES POR CORONAVIRUS ,Haplotype ,Immunogenetics ,Major histocompatibility complex ,Asymptomatic ,Cell killing ,Genotype ,Immunology ,medicine ,biology.protein ,Cytotoxic T cell ,medicine.symptom ,Gene - Abstract
BackgroundDespite the high number of individuals infected by SARS-CoV-2 who develop COVID-19 symptoms worldwide, many exposed individuals remain asymptomatic and/or stay uninfected. This could be explained by a combination of environmental (exposure, previous infection), epigenetic, and genetic factors. Aiming to identify genetic variants involved in SARS-CoV-2 resistance, we analyzed 86 discordant Brazilian couples where one was infected and symptomatic while the partner remained asymptomatic and seronegative despite sharing the same bedroom during the infection. The discordant partners had comparable ages, and genetic ancestry proportions.MethodsWhole-exome sequencing followed by a state-of-the-art method to call genotypes and haplotypes across the highly polymorphic MHC and LRC.ResultsWe observed a minor impact in antigen-presentation genes and KIR genes associated with resistance. Interestingly, genes related to immune modulation, mainly involved in NK cell killing activation/inhibition harbor variants potentially contributing to infection resistance. We hypothesize that individuals prone to produce higher amounts of MICA (possibly soluble), LILRB1, LILRB2, and low amounts of MICB, would be more susceptible to infection.ConclusionAccording to this hypothesis, quantitative differences in these NK activity-related molecules could contribute to resistance to COVID-19 down regulating NK cell cytotoxic activity in infected individuals but not in resistant partners.
- Published
- 2021
22. Monozygotic twins discordant for severe clinical recurrence of COVID-19 show drastically distinct T cell responses to SARS-Cov-2
- Author
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Marilia O. Scliar, Mayana Zatz, Miguel Mitne Neto, Bruni M, Jacintho Lc, Edgar Ruz Fernandes, Michel S Naslavsky, Antonio Carlos Pedroso de Lima, Matos Lrb, Marcio Massao Yamamoto, Erick C. Castelli, Andréia Kuramoto, Maciel Rmb, S. Nunes Jp, Maria Rita Passos-Bueno, F.R. Bruno, Jorge Kalil, Edecio Cunha-Neto, Silva Mvr, Levin G, Kelly Nunes, Silvia Beatriz Boscardin, Juliana de Souza Apostólico, Verônica Coelho, Castro MVd, Daniela Santoro Rosa, Keity Souza Santos, Wang Jyt, Rafael Ribeiro Almeida, Jhosiene Y. Magawa, and Vivian R. Coria
- Subjects
biology ,business.industry ,T cell ,ELISPOT ,TRANSMISSÃO DE DOENÇAS ,Monozygotic twin ,Acquired immune system ,Immune system ,medicine.anatomical_structure ,Interferon ,Immunology ,biology.protein ,Medicine ,Antibody ,business ,Neutralizing antibody ,medicine.drug - Abstract
BackgroundClinical recurrence of COVID-19 in convalescent patients has been reported, which immune mechanisms have not been thoroughly investigated. Presence of neutralizing antibodies suggests other types of immune response are involved.MethodsWe assessed the innate type I/III IFN response, T cell responses to SARS-CoV-2 with IFNγ ELISPOT, binding and neutralizing antibody assays, in two monozygotic twin pairs with one COVID-19 recurrence case.ResultsIn pair 1, four months after a first mild episode of infection for both siblings, one displayed severe clinical recurrence of COVID-19. Twin pair 2 of siblings underwent non-recurring asymptomatic infection. All fours individuals presented similar overall responses, except for remarkably difference found in specific cellular responses. Recurring sibling presented a reduced number of recognized T cell epitopes as compared to the other three including her non-recurring sibling.ConclusionsOur results suggest that an effective SARS-CoV-2-specific T cell immune response is key for complete viral control and avoidance of clinical recurrence of COVID-19. Besides, adaptive immunity can be distinct in MZ twins. Given the rising concern about SARS-CoV-2 variants that evade neutralizing antibodies elicited by vaccination or infection, our study stresses the importance of T cell responses in protection against recurrence/reinfection.Key pointsImmune parameters leading to COVID-19 recurrence/reinfection are incompletely understood. A COVID-19 recurrence case in a monozygotic twin pair is described with an intact antibody and innate type I/III Interferon response and drastically reduced number of recognized SARS-CoV-2 T cell epitopes.
- Published
- 2021
23. Rare Variant Burden Analysis within Enhancers Identifies CAV1 as an ALS Risk Gene
- Author
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Johnathan Cooper-Knock, Sai Zhang, Kevin P. Kenna, Tobias Moll, John P. Franklin, Samantha Allen, Helia Ghahremani Nezhad, Alfredo Iacoangeli, Nancy Y. Yacovzada, Chen Eitan, Eran Hornstein, Eran Elhaik, Petra Celadova, Daniel Bose, Sali Farhan, Simon Fishilevich, Doron Lancet, Karen E. Morrison, Christopher E. Shaw, Ammar Al-Chalabi, Jan H. Veldink, Janine Kirby, Michael P. Snyder, Pamela J. Shaw, Ian Blair, Naomi Wray, Matthew Kiernan, Miguel Mitne Neto, Adriano Chio, Ruben Cauchi, Wim Robberecht, Philip van Damme, Phillippe Corcia, Phillipe Couratier, Orla Hardiman, Russel McLaughlin, Marc Gotkine, Vivan Drory, Nicola Ticozzi, Vincenzo Silani, Jan Veldink, Leonard van den Berg, Mamede de Carvalho, Jesus Mora Pardina, Monica Povedano, Peter Andersen, Markus Wber, Nazli Başak, Christopher Shaw, Pamela Shaw, Karen Morrison, John Landers, Jonathan Glass, and Project MinE ALS Sequencing Consortium
- Subjects
0301 basic medicine ,SELECTION ,amyotrophic lateral sclerosis ,CAV1 ,CAV2 ,gene enhancers ,membrane lipid rafts ,non-coding DNA ,whole-genome sequencing ,Caveolin 1 ,Genome ,AMYOTROPHIC-LATERAL-SCLEROSIS ,DISEASE ,Exon ,TOXIN B-SUBUNIT ,0302 clinical medicine ,Gene expression ,Amyotrophic lateral sclerosis ,Membrane lipids -- Research ,lcsh:QH301-705.5 ,Genetics ,ASSOCIATION ,Phenotype ,GENOME ,Medical genetics ,AUTOPHAGY ,Life Sciences & Biomedicine ,medicine.medical_specialty ,Biology ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Amyotrophic lateral sclerosis -- Diagnosis ,Report ,medicine ,Animals ,Humans ,RECONSTRUCTION ,Genetic Predisposition to Disease ,Enhancer ,Non-coding RNA ,Genetic association ,Science & Technology ,Correction ,Genetic Variation ,Cell Biology ,medicine.disease ,DYSFUNCTION ,NEUROTROPHIN RECEPTOR ,030104 developmental biology ,Genes ,lcsh:Biology (General) ,030217 neurology & neurosurgery - Abstract
Summary Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease. CAV1 and CAV2 organize membrane lipid rafts (MLRs) important for cell signaling and neuronal survival, and overexpression of CAV1 ameliorates ALS phenotypes in vivo. Genome-wide association studies localize a large proportion of ALS risk variants within the non-coding genome, but further characterization has been limited by lack of appropriate tools. By designing and applying a pipeline to identify pathogenic genetic variation within enhancer elements responsible for regulating gene expression, we identify disease-associated variation within CAV1/CAV2 enhancers, which replicate in an independent cohort. Discovered enhancer mutations reduce CAV1/CAV2 expression and disrupt MLRs in patient-derived cells, and CRISPR-Cas9 perturbation proximate to a patient mutation is sufficient to reduce CAV1/CAV2 expression in neurons. Additional enrichment of ALS-associated mutations within CAV1 exons positions CAV1 as an ALS risk gene. We propose CAV1/CAV2 overexpression as a personalized medicine target for ALS., Graphical Abstract, Highlights • Identification of ALS-associated genetic variation within gene enhancers • ALS-associated risk variants identified within enhancers and exons linked to CAV1 • CAV1/CAV2 enhancer mutations reduce gene expression and disrupt membrane lipid rafts • CRISPR-Cas9 perturbation of enhancer reduces CAV1/CAV2 expression in neurons, Cooper-Knock et al. identify amyotrophic lateral sclerosis (ALS) risk variants within non-coding regulatory DNA linked to a known ALS gene, TBK1, but also CAV1 and CAV2. Disease-associated variants reduce CAV1/CAV2 expression and disrupt membrane lipid rafts with consequences for neurotrophic signaling. CAV1 coding sequence also contains ALS-associated mutations.
- Published
- 2020
24. Diagnostic power and clinical impact of exome sequencing in a cohort of 500 patients with rare diseases
- Author
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Rodrigo Fernandes Ramalho, Michele Groenner Penna, Wagner A.R. Baratela, Shirley Dezan Matalhana, Cintia Reys Furuzawa, Ana Lígia Buzolin, Gil M. Novo-Filho, Maria de Lourdes Lopes Ferrari Chauffaille, Aurelio Pimenta Dutra, Gustavo Marquezani Spolador, Vinícius Ceola Pereira, Aline Dos Santos Borgo Perazzio, Chong Ae Kim, Otavio Jose Eulalio Pereira, Ana Lúcia Catelani, Alexandre Ricardo dos Santos Fornari, Monize Nakamoto Provisor Santos, Javier Miguelez, Vanessa Galdeno Freitas, Vanessa Dionisio Cantagalli, Ana Carolina Gomes Trindade, Patricia Rossi Sacramento-Bobotis, Daniele Paixão, Caroline Olivati, Gustavo Arantes Rosa Maciel, Caio Robledo D'Angioli Costa Quaio, Mário Henrique Burlacchini de Carvalho, Elisa Napolitano Ferreira, Fernanda Verzini, Rafael Alves da Silva, Vanessa Yurie Nozaki de Arruda, David Santos Marco Antonio, Alexandre Wagner Silva de Souza, Naiade Romano, Viviane Z. Rocha, Caroline Monaco Moreira, Rafaela Rogerio Floriano de Sousa, Miguel Mitne-Neto, Matheus Carvalho Bürger, Sandro Félix Perazzio, Luis Eduardo Coelho Andrade, Maria Carolina Pintao, and Andre Yuji Oku
- Subjects
0301 basic medicine ,medicine.medical_specialty ,medicine.medical_treatment ,Consanguinity ,030105 genetics & heredity ,Targeted therapy ,Cohort Studies ,03 medical and health sciences ,Liver disease ,Rare Diseases ,Pregnancy ,Internal medicine ,Exome Sequencing ,Genetics ,Medicine ,Humans ,Exome ,Clinical care ,Child ,Genetics (clinical) ,Exome sequencing ,business.industry ,medicine.disease ,030104 developmental biology ,Cohort ,Life expectancy ,Female ,business - Abstract
Rare diseases comprise a diverse group of conditions, most of which involve genetic causes. We describe the variable spectrum of findings and clinical impacts of exome sequencing (ES) in a cohort of 500 patients with rare diseases. In total, 164 primary findings were reported in 158 patients, representing an overall diagnostic yield of 31.6%. Most of the findings (61.6%) corresponded to autosomal dominant conditions, followed by autosomal recessive (25.6%) and X-linked (12.8%) conditions. These patients harbored 195 variants, among which 43.6% are novel in the literature. The rate of molecular diagnosis was considerably higher for prenatal samples (67%; 4/6), younger children (44%; 24/55), consanguinity (50%; 3/6), gastrointestinal/liver disease (44%; 16/36) and syndromic/malformative conditions (41%; 72/175). For 15.6% of the cohort patients, we observed a direct potential for the redirection of care with targeted therapy, tumor screening, medication adjustment and monitoring for disease-specific complications. Secondary findings were reported in 37 patients (7.4%). Based on cost-effectiveness studies in the literature, we speculate that the reports of secondary findings may influence an increase of 123.2 years in the life expectancy for our cohort, or 0.246 years/cohort patient. ES is a powerful method to identify the molecular bases of monogenic disorders and redirect clinical care.
- Published
- 2020
25. Mutational Profiling of Acute Myeloid Leukemia with Normal Cytogenetics in Brazilian Patients: The Value of Next-Generation Sequencing for Genomic Classification
- Author
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Maria de Lourdes Lopes Ferrari Chauffaille, Thiago Rodrigo de Noronha, and Miguel Mitne-Neto
- Subjects
Male ,0301 basic medicine ,Neuroblastoma RAS viral oncogene homolog ,NPM1 ,medicine.medical_specialty ,Biology ,medicine.disease_cause ,Polymorphism, Single Nucleotide ,General Biochemistry, Genetics and Molecular Biology ,Cytogenetics ,03 medical and health sciences ,0302 clinical medicine ,CEBPA ,medicine ,Humans ,Genetic Predisposition to Disease ,Genetics ,High-Throughput Nucleotide Sequencing ,Myeloid leukemia ,Genomics ,General Medicine ,Middle Aged ,Prognosis ,medicine.disease ,Uniparental disomy ,Leukemia, Myeloid, Acute ,030104 developmental biology ,030220 oncology & carcinogenesis ,Mutation ,DNA methylation ,Female ,KRAS ,Nucleophosmin ,Brazil - Abstract
Karyotype (KT) aberrations are important prognostic factors for acute myeloid leukemia (AML); however, around 50% of cases present normal results. Single nucleotide polymorphism array can detect chromosomal gains, losses or uniparental disomy that are invisible to KT, thus improving patients’ risk assessment. However, when both tests are normal, important driver mutations can be detected by the use of next-generation sequencing (NGS). Fourteen adult patients with AML with normal cytogenetics were investigated by NGS for 19 AML-related genes. Every patient presented at least one mutation: DNMT3A in nine patients; IDH2 in six; IDH1 in three; NRAS and NPM1 in two; and TET2, ASXL1, PTPN11, and RUNX1 in one patient. No mutations were found in FLT3, KIT, JAK2, CEBPA, GATA2, TP53, BRAF, CBL, KRAS, and WT1 genes. Twelve patients (86%) had at least one mutation in genes related with DNA methylation ( DNMT3A, IDH1, IDH2, and TET2), which is involved in regulation of gene expression and genomic stability. All patients could be reclassified based on genomic status and nine had their prognosis modified. In summary, NGS offers insights into the molecular pathogenesis and biology of cytogenetically normal AML in Brazilian patients, indicating that the prognosis could be further stratified by different mutation combinations. This study shows a different frequency of mutations in Brazilian population that should be confirmed.
- Published
- 2017
26. A Novel Saliva RT-LAMP Workflow for Rapid Identification of COVID-19 Cases and Restraining Viral Spread
- Author
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Natale Cavaçana, Naila Cristina Vilaça Lourenço, Marcelo Andreetta Corral, Maria Cassia Mendes-Correa, Luciano Abreu Brito, Gabriella Shih Ping Hsia, Erika R. Manuli, Alvaro Razuk Filho, Chuck S. Farah, Ana Paula Barreto de Paiva, Maria Mirtes Sales, Beatriz Araujo Oliveira, Luiz Phellipe Dell' Aquila, Miguel Mitne-Neto, Angela May Suzuki, Maria Rita Passos-Bueno, Mayana Zatz, Lylyan Fragoso Pimentel, Germán G. Sgro, Gerson Shigeru Kobayashi, Carolina Regoli Dias, Eduardo Fagundes Parrillo, Danielle de Paula Moreira, Ester Cerdeira Sabino, Fabio E. Leal, and Silvia Figueiredo Costa
- Subjects
0301 basic medicine ,Medicine (General) ,Saliva ,Coronavirus disease 2019 (COVID-19) ,viral diagnostics ,Clinical Biochemistry ,NOP ,Loop-mediated isothermal amplification ,Article ,law.invention ,03 medical and health sciences ,R5-920 ,0302 clinical medicine ,law ,Medicine ,030212 general & internal medicine ,2019 novel coronavirus ,saliva ,LAMP (loop-mediated isothermal amplification) assay ,business.industry ,TRANSMISSÃO DE DOENÇAS ,030104 developmental biology ,Transmission (mechanics) ,Immunology ,Viral spread ,business ,Viral load ,Kappa - Abstract
Rapid diagnostics is pivotal to curb SARS-CoV-2 transmission, and saliva has emerged as a practical alternative to naso/oropharyngeal (NOP) specimens. We aimed to develop a direct RT-LAMP (reverse transcription loop-mediated isothermal amplification) workflow for viral detection in saliva, and to provide more information regarding its potential in curbing COVID-19 transmission. Clinical and contrived specimens were used to optimize formulations and sample processing protocols. Salivary viral load was determined in symptomatic patients to evaluate the clinical performance of the test and to characterize saliva based on age, gender and time from onset of symptoms. Our workflow achieved an overall sensitivity of 77.2% (n = 90), with 93.2% sensitivity, 97% specificity, and 0.895 Kappa for specimens containing >, 102 copies/μL (n = 77). Further analyses in saliva showed that viral load peaks in the first days of symptoms and decreases afterwards, and that viral load is ~10 times lower in females compared to males, and declines following symptom onset. NOP RT-PCR data did not yield relevant associations. This work suggests that saliva reflects the transmission dynamics better than NOP specimens, and reveals gender differences that may reflect higher transmission by males. This saliva RT-LAMP workflow can be applied to track viral spread and, to maximize detection, testing should be performed immediately after symptoms are presented, especially in females.
- Published
- 2021
27. DUOX2 Mutations Are Associated With Congenital Hypothyroidism With Ectopic Thyroid Gland
- Author
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Corinne Dupuy, Denise P. Carvalho, Magnus R. Dias-da-Silva, Jessica R Jara, Miguel Mitne-Neto, Rui M. B. Maciel, Suzana Nesi-França, Gilberto K. Furuzawa, Marina M. L. Kizys, Ruy A. N. Louzada, Institut Gustave Roussy (IGR), Stabilité Génétique et Oncogenèse (UMR 8200), and Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Candidate gene ,Endocrinology, Diabetes and Metabolism ,DNA Mutational Analysis ,Clinical Biochemistry ,Thyroid Gland ,Context (language use) ,medicine.disease_cause ,Biochemistry ,Thyroid dysgenesis ,Cohort Studies ,03 medical and health sciences ,symbols.namesake ,Endocrinology ,Protein Domains ,Internal medicine ,Congenital Hypothyroidism ,medicine ,Humans ,Genetic Predisposition to Disease ,ComputingMilieux_MISCELLANEOUS ,Genetic Association Studies ,Congenital Hypothyroidism with Ectopic Thyroid ,Sanger sequencing ,Mutation ,business.industry ,Biochemistry (medical) ,Thyroid ,Infant, Newborn ,[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,medicine.disease ,Dual Oxidases ,3. Good health ,Congenital hypothyroidism ,HEK293 Cells ,030104 developmental biology ,medicine.anatomical_structure ,Thyroid Dysgenesis ,symbols ,Female ,business - Abstract
Context Thyroid dysgenesis (TD) is the leading cause of congenital hypothyroidism (CH). The etiology of TD remains unknown in ∼90% of cases, the most common form being thyroid ectopia (TE) (48% to 61%). Objective To search for candidate genes in hypothyroid children with TE. Design, Setting, and Participants We followed a cohort of 268 children with TD and performed whole-exome sequencing (WES) in three children with CH with TE (CHTE) and compared them with 18 thyroid-healthy controls. We then screened an additional 41 children with CHTE by Sanger sequencing and correlated the WES and Sanger molecular findings with in vitro functional analysis. Main Outcome Measures Genotyping, mutation prediction analysis, and in vitro functional analysis. Results We identified seven variants in the DUOX2 gene, namely G201E, L264CfsX57, P609S, M650T, E810X, M822V, and E1017G, and eight known variations. All children carrying DUOX2 variations had high thyroid-stimulating hormone levels at neonatal diagnosis. All mutations were localized in the N-terminal segment, and three of them led to effects on cell surface targeting and reactive oxygen species generation. The DUOX2 mutants also altered the interaction with the maturation factor DUOXA2 and the formation of a stable DUOX2/DUOXA2 complex at the cell surface, thereby impairing functional enzymatic activity. We observed no mutations in the classic genes related to TD or in the DUOX1 gene. Conclusion Our findings suggest that, in addition to thyroid hormonogenesis, the DUOX2 N-terminal domain may play a role in thyroid development.
- Published
- 2017
28. Development and validation of a variant detection workflow for BRCA1 and BRCA2 genes and its clinical application based on the Ion Torrent technology
- Author
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Caio Robledo D'Angioli Costa Quaio, Caroline Monaco Moreira, David Santos Marco Antonio, Miguel Mitne-Neto, Ana Lígia Buzolin, Patricia Rossi Sacramento, Alexandre Ricardo dos Santos Fornari, Andre Yuji Oku, and Wagner A.R. Baratela
- Subjects
0301 basic medicine ,lcsh:QH426-470 ,Genetic counseling ,BRCA ,lcsh:Medicine ,Breast Neoplasms ,Computational biology ,Bioinformatics ,Ion Torrent ,Workflow ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Drug Discovery ,Genetics ,medicine ,Humans ,Multiplex ,Breast ,skin and connective tissue diseases ,Molecular Biology ,Cancer ,BRCA2 Protein ,Ovarian Neoplasms ,BRCA1 Protein ,business.industry ,lcsh:R ,Computational Biology ,Sequence Analysis, DNA ,Ion semiconductor sequencing ,medicine.disease ,Human genetics ,lcsh:Genetics ,030104 developmental biology ,Ovarian ,030220 oncology & carcinogenesis ,Mutation ,Molecular Medicine ,Female ,Primary Research ,business ,Ovarian cancer - Abstract
Background Breast cancer is the most common among women worldwide, and ovarian cancer is the most difficult gynecological tumor to diagnose and with the lowest chance of cure. Mutations in BRCA1 and BRCA2 genes increase the risk of ovarian cancer by 60% and breast cancer by up to 80% in women. Molecular tests allow a better orientation for patients carrying these mutations, affecting prophylaxis, treatment, and genetic counseling. Results Here, we evaluated the performance of a panel for BRCA1 and BRCA2, using the Ion Torrent PGM (Life Technologies) platform in a customized workflow and multiplex ligation-dependent probe amplification for detection of mutations, insertions, and deletions in these genes. We validated the panel with 26 samples previously analyzed by Myriad Genetics Laboratory, and our workflow showed 95.6% sensitivity and 100% agreement with Myriad reports, with 85% sensitivity on the positive control sample from NIST. We also screened 68 clinical samples and found 22 distinct mutations. Conclusions The selection of a robust methodology for sample preparation and sequencing, together with bioinformatics tools optimized for the data analysis, enabled the development of a very sensitive test with high reproducibility. We also highlight the need to explore the limitations of the NGS technique and the strategies to overcome them in a clinically confident manner. Electronic supplementary material The online version of this article (doi:10.1186/s40246-017-0110-x) contains supplementary material, which is available to authorized users.
- Published
- 2017
29. Diagnostic power and clinical impact of exome sequencing in a cohort of 500 patients with rare diseases
- Author
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Gil Monteiro Novo Filho, Caroline Monaco Moreira, Caio Robledo D'Angioli Costa Quaio, Chong Ae Kim, Aurelio Pimenta Dutra, Rodrigo Fernandes Ramalho, Rafaela Rogerio Floriano de Sousa, Miguel Mitne-Neto, Patricia Rossi Sacramento-Bobo, Sandro Félix Perazzio, Rafael Alves da Silva, Michele Groenner Penna, and Wagner A.R. Baratela
- Subjects
Pediatrics ,medicine.medical_specialty ,Endocrinology ,business.industry ,Endocrinology, Diabetes and Metabolism ,Cohort ,Genetics ,medicine ,business ,Molecular Biology ,Biochemistry ,Exome sequencing - Published
- 2021
30. The Project MinE databrowser: bringing large-scale whole-genome sequencing in ALS to researchers and the public
- Author
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Gijs H.P. Tazelaar, Yolanda Campos, Pamela J. Shaw, Rick A.A. van der Spek, Ammar Al-Chalabi, Ian R. A. Mackenzie, John Landers, Mónica Povedano Panades, Ceren Tunca, Johnathan Cooper-Knock, Karen E. Morrison, Orla Hardiman, Janez Zidar, Vivian E. Drory, Atay Vural, Vera Fominyh, Kristel R. van Eijk, Raymond D. Schellevis, Ahmad Al Khleifat, Phillipe Corcia, Ersen Kavak, Stephan Newhouse, Mamede de Carvalho, Kevin P. Kenna, Sara L. Pulit, William J. Brands, Nazli Basak, Marc Gotkine, Gabriel Miltenberger-Miltenyi, Matthieu Moisse, Jesus S. Mora, Annelot M. Dekker, Joke J.F.A. van Vugt, Boris Rogelj, Philip Van Damme, Wim Robberecht, Ervina Bilić, Maarten Kooyman, William Sproviero, Nicolas Dupré, Blaz Koritnik, Tuncay Seker, Leonard H. van den Berg, Jan H. Veldink, Ross P. Byrne, Brendan J. Kenna, Naomi R. Wray, P. Couratier, Perry T.C. van Doormaal, Jonathan D. Glass, Johnathan Mill, Russell L. McLaughlin, Bas Middelkoop, Lev Brylev, Alberto Garcia Redondo, Nicola Ticozzi, Markus Weber, Wouter van Rheenen, Mayana Zatz, Christopher Shaw, Cemile Kocoglu, Ivana Munitic, Ekaterina Rogaeva, Miguel Mitne-Neto, Peter M. Andersen, Vincenzo Silani, Michael A. van Es, Fulya Akçimen, Aleksey Shatunov, Matthew C. Kiernan, Ian P. Blair, Guy A. Rouleau, Adriano Chiò, Alfredo Iacoangeli, and Victoria Lopez Alonso
- Subjects
Whole genome sequencing ,Resource (project management) ,Computer science ,Project MinE ,Scale (social sciences) ,Genetic variation ,Genomics ,Biostatistics ,Set (psychology) ,Data science - Abstract
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive fatal neurodegenerative disease affecting 1 in 350 people. The aim of Project MinE is to elucidate the pathophysiology of ALS through whole-genome sequencing at least 15,000 ALS patients and 7,500 controls at 30X coverage. Here, we present the Project MinE data browser (databrowser.projectmine.com). a unique and intuitive one-stop, open-access server that provides detailed information on genetic variation analyzed in a new and still growing set of 4,366 ALS cases and 1,832 matched controls. Through its visual components and interactive design, the browser specifically aims to be a resource to those without a biostatistics background and allow clinicians and preclinical researchers to integrate Project MinE data into their own research. The browser allows users to query a transcript and immediately access a unique combination of detailed (meta)data, annotations and association statistics that would otherwise require analytic expertise and visits to scattered resources.
- Published
- 2018
31. Genome-wide Analyses Identify KIF5A as a Novel ALS Gene
- Author
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Aude Nicolas, Kevin P. Kenna, Alan E. Renton, Nicola Ticozzi, Faraz Faghri, Ruth Chia, Janice A. Dominov, Brendan J. Kenna, Mike A. Nalls, Pamela Keagle, Alberto M. Rivera, Wouter van Rheenen, Natalie A. Murphy, Joke J.F.A. van Vugt, Joshua T. Geiger, Rick A. Van der Spek, Hannah A. Pliner, null Shankaracharya, Bradley N. Smith, Giuseppe Marangi, Simon D. Topp, Yevgeniya Abramzon, Athina Soragia Gkazi, John D. Eicher, Aoife Kenna, Gabriele Mora, Andrea Calvo, Letizia Mazzini, Nilo Riva, Jessica Mandrioli, Claudia Caponnetto, Stefania Battistini, Paolo Volanti, Vincenzo La Bella, Francesca L. Conforti, Giuseppe Borghero, Sonia Messina, Isabella L. Simone, Francesca Trojsi, Fabrizio Salvi, Francesco O. Logullo, Sandra D’Alfonso, Lucia Corrado, Margherita Capasso, Luigi Ferrucci, Cristiane de Araujo Martins Moreno, Sitharthan Kamalakaran, David B. Goldstein, Aaron D. Gitler, Tim Harris, Richard M. Myers, Hemali Phatnani, Rajeeva Lochan Musunuri, Uday Shankar Evani, Avinash Abhyankar, Michael C. Zody, Julia Kaye, Steven Finkbeiner, Stacia K. Wyman, Alex LeNail, Leandro Lima, Ernest Fraenkel, Clive N. Svendsen, Leslie M. Thompson, Jennifer E. Van Eyk, James D. Berry, Timothy M. Miller, Stephen J. Kolb, Merit Cudkowicz, Emily Baxi, Michael Benatar, J. Paul Taylor, Evadnie Rampersaud, Gang Wu, Joanne Wuu, Giuseppe Lauria, Federico Verde, Isabella Fogh, Cinzia Tiloca, Giacomo P. Comi, Gianni Sorarù, Cristina Cereda, Philippe Corcia, Hannu Laaksovirta, Liisa Myllykangas, Lilja Jansson, Miko Valori, John Ealing, Hisham Hamdalla, Sara Rollinson, Stuart Pickering-Brown, Richard W. Orrell, Katie C. Sidle, Andrea Malaspina, John Hardy, Andrew B. Singleton, Janel O. Johnson, Sampath Arepalli, Peter C. Sapp, Diane McKenna-Yasek, Meraida Polak, Seneshaw Asress, Safa Al-Sarraj, Andrew King, Claire Troakes, Caroline Vance, Jacqueline de Belleroche, Frank Baas, Anneloor L.M.A. ten Asbroek, José Luis Muñoz-Blanco, Dena G. Hernandez, Jinhui Ding, J. Raphael Gibbs, Sonja W. Scholz, Mary Kay Floeter, Roy H. Campbell, Francesco Landi, Robert Bowser, Stefan M. Pulst, John M. Ravits, Daniel J.L. MacGowan, Janine Kirby, Erik P. Pioro, Roger Pamphlett, James Broach, Glenn Gerhard, Travis L. Dunckley, Christopher B. Brady, Neil W. Kowall, Juan C. Troncoso, Isabelle Le Ber, Kevin Mouzat, Serge Lumbroso, Terry D. Heiman-Patterson, Freya Kamel, Ludo Van Den Bosch, Robert H. Baloh, Tim M. Strom, Thomas Meitinger, Aleksey Shatunov, Kristel R. Van Eijk, Mamede de Carvalho, Maarten Kooyman, Bas Middelkoop, Matthieu Moisse, Russell L. McLaughlin, Michael A. Van Es, Markus Weber, Kevin B. Boylan, Marka Van Blitterswijk, Rosa Rademakers, Karen E. Morrison, A. Nazli Basak, Jesús S. Mora, Vivian E. Drory, Pamela J. Shaw, Martin R. Turner, Kevin Talbot, Orla Hardiman, Kelly L. Williams, Jennifer A. Fifita, Garth A. Nicholson, Ian P. Blair, Guy A. Rouleau, Jesús Esteban-Pérez, Alberto García-Redondo, Ammar Al-Chalabi, Ekaterina Rogaeva, Lorne Zinman, Lyle W. Ostrow, Nicholas J. Maragakis, Jeffrey D. Rothstein, Zachary Simmons, Johnathan Cooper-Knock, Alexis Brice, Stephen A. Goutman, Eva L. Feldman, Summer B. Gibson, Franco Taroni, Antonia Ratti, Cinzia Gellera, Philip Van Damme, Wim Robberecht, Pietro Fratta, Mario Sabatelli, Christian Lunetta, Albert C. Ludolph, Peter M. Andersen, Jochen H. Weishaupt, William Camu, John Q. Trojanowski, Vivianna M. Van Deerlin, Robert H. Brown, Leonard H. van den Berg, Jan H. Veldink, Matthew B. Harms, Jonathan D. Glass, David J. Stone, Pentti Tienari, Vincenzo Silani, Adriano Chiò, Christopher E. Shaw, Bryan J. Traynor, John E. Landers, Isabella Simone, Giancarlo Logroscino, Ilaria Bartolomei, Maria Rita Murru, Emanuela Costantino, Carla Pani, Roberta Puddu, Carla Caredda, Valeria Piras, Stefania Tranquilli, Stefania Cuccu, Daniela Corongiu, Maurizio Melis, Antonio Milia, Francesco Marrosu, Maria Giovanna Marrosu, Gianluca Floris, Antonino Cannas, Gianluigi Mancardi, Paola Origone, Paola Mandich, Sebastiano Cavallaro, Kalliopi Marinou, Riccardo Sideri, Silvana Penco, Lorena Mosca, Giuseppe Lauria Pinter, Massimo Corbo, Paola Carrera, Nicola Fini, Antonio Fasano, Lucio Tremolizzo, Alessandro Arosio, Carlo Ferrarese, Gioacchino Tedeschi, Maria Rosaria Monsurrò, Giovanni Piccirillo, Cinzia Femiano, Anna Ticca, Enzo Ortu, Rossella Spataro, Tiziana Colletti, Marcella Zollino, Amelia Conte, Marco Luigetti, Serena Lattante, Marialuisa Santarelli, Antonio Petrucci, Maura Pugliatti, Angelo Pirisi, Leslie D. Parish, Patrizia Occhineri, Fabio Giannini, Claudia Ricci, Michele Benigni, Tea B. Cau, Daniela Loi, Cristina Moglia, Maura Brunetti, Marco Barberis, Gabriella Restagno, Federico Casale, Giuseppe Marrali, Giuseppe Fuda, Irene Ossola, Stefania Cammarosano, Antonio Canosa, Antonio Ilardi, Umberto Manera, Maurizio Grassano, Raffaella Tanel, Fabrizio Pisano, Neil A. Shneider, Stephen Goutman, Siddharthan Chandran, Suvankar Pal, George Manousakis, Stanley H. Appel, Ericka Simpson, Leo Wang, Summer Gibson, Richard Bedlack, David Lacomis, Dhruv Sareen, Alexander Sherman, Lucie Bruijn, Michelle Penny, Andrew S. Allen, Stanley Appel, Richard S. Bedlack, Braden E. Boone, Robert Brown, John P. Carulli, Alessandra Chesi, Wendy K. Chung, Elizabeth T. Cirulli, Gregory M. Cooper, Julien Couthouis, Aaron G. Day-Williams, Patrick A. Dion, Yujun Han, Sebastian D. Hayes, Angela L. Jones, Jonathan Keebler, Brian J. Krueger, Brittany N. Lasseigne, Shawn E. Levy, Yi-Fan Lu, Tom Maniatis, Slavé Petrovski, Alya R. Raphael, Zhong Ren, Katherine B. Sims, John F. Staropoli, Lindsay L. Waite, Quanli Wang, Jack R. Wimbish, Winnie W. Xin, Justin Kwan, James R. Broach, Ximena Arcila-Londono, Edward B. Lee, Noah Zaitlen, Gregory A. Cox, Steve Finkbeiner, Efthimios Dardiotis, Eran Hornstein, Daniel J. MacGowan, Terry Heiman-Patterson, Molly G. Hammell, Nikolaos A. Patsopoulos, Joshua Dubnau, Avindra Nath, Stacia Wyman, Alexander LeNail, Jenny Van Eyk, Stephan Züchner, Rebecca Schule, Jacob McCauley, Sumaira Hussain, Anne Cooley, Marielle Wallace, Christine Clayman, Richard Barohn, Jeffrey Statland, John Ravits, Andrea Swenson, Carlayne Jackson, Jaya Trivedi, Shaida Khan, Jonathan Katz, Liberty Jenkins, Ted Burns, Kelly Gwathmey, James Caress, Corey McMillan, Lauren Elman, Erik Pioro, Jeannine Heckmann, Yuen So, David Walk, Samuel Maiser, Jinghui Zhang, Fabiola De Marchi, Stefania Corti, Mauro Ceroni, Gabriele Siciliano, Massimiliano Filosto, Maurizio Inghilleri, Silvia Peverelli, Claudia Colombrita, Barbara Poletti, Luca Maderna, Roberto Del Bo, Stella Gagliardi, Giorgia Querin, Cinzia Bertolin, Viviana Pensato, Barbara Castellotti, Vincent Meininger, Gérard Besson, Emmeline Lagrange, Pierre Clavelou, Nathalie Guy, Philippe Couratier, Patrick Vourch, Véronique Danel, Emilien Bernard, Gwendal Lemasson, Ahmad Al Kheifat, Peter Andersen, Adriano Chio, Jonathan Cooper-Knock, Annelot Dekker, Vivian Drory, Alberto Garcia Redondo, Marc Gotkine, Winston Hide, Alfredo Iacoangeli, Jonathan Glass, Kevin Kenna, Matthew Kiernan, John Landers, Russell McLaughlin, Jonathan Mill, Miguel Mitne Neto, Mattieu Moisse, Jesus Mora Pardina, Karen Morrison, Stephen Newhouse, Susana Pinto, Sara Pulit, Pamela Shaw, Chris Shaw, William Sproviero, Gijs Tazelaar, Philip van Damme, Leonard van den Berg, Rick van der Spek, Kristel van Eijk, Michael van Es, Joke van Vugt, Jan Veldink, Mayana Zatz, Denis C. Bauer, Natalie A. Twine, Department of Neurosciences, Pentti Tienari / Principal Investigator, Neurologian yksikkö, Research Programs Unit, Clinicum, Research Programme for Molecular Neurology, University of Helsinki, Medicum, Department of Pathology, HUS Neurocenter, Nicolas A., Kenna K.P., Renton A.E., Ticozzi N., Faghri F., Chia R., Dominov J.A., Kenna B.J., Nalls M.A., Keagle P., Rivera A.M., van Rheenen W., Murphy N.A., van Vugt J.J.F.A., Geiger J.T., Van der Spek R.A., Pliner H.A., Shankaracharya, Smith B.N., Marangi G., Topp S.D., Abramzon Y., Gkazi A.S., Eicher J.D., Kenna A., Logullo F.O., Simone I.L., Logroscino G., Salvi F., Bartolomei I., Borghero G., Murru M.R., Costantino E., Pani C., Puddu R., Caredda C., Piras V., Tranquilli S., Cuccu S., Corongiu D., Melis M., Milia A., Marrosu F., Marrosu M.G., Floris G., Cannas A., Capasso M., Caponnetto C., Mancardi G., Origone P., Mandich P., Conforti F.L., Cavallaro S., Mora G., Marinou K., Sideri R., Penco S., Mosca L., Lunetta C., Pinter G.L., Corbo M., Riva N., Carrera P., Volanti P., Mandrioli J., Fini N., Fasano A., Tremolizzo L., Arosio A., Ferrarese C., Trojsi F., Tedeschi G., Monsurro M.R., Piccirillo G., Femiano C., Ticca A., Ortu E., La Bella V., Spataro R., Colletti T., Sabatelli M., Zollino M., Conte A., Luigetti M., Lattante S., Santarelli M., Petrucci A., Pugliatti M., Pirisi A., Parish L.D., Occhineri P., Giannini F., Battistini S., Ricci C., Benigni M., Cau T.B., Loi D., Calvo A., Moglia C., Brunetti M., Barberis M., Restagno G., Casale F., Marrali G., Fuda G., Ossola I., Cammarosano S., Canosa A., Ilardi A., Manera U., Grassano M., Tanel R., Pisano F., Mazzini L., Messina S., D'Alfonso S., Corrado L., Ferrucci L., Harms M.B., Goldstein D.B., Shneider N.A., Goutman S.A., Simmons Z., Miller T.M., Chandran S., Pal S., Manousakis G., Appel S.H., Simpson E., Wang L., Baloh R.H., Gibson S.B., Bedlack R., Lacomis D., Sareen D., Sherman A., Bruijn L., Penny M., Moreno C.D.A.M., Kamalakaran S., Allen A.S., Boone B.E., Brown R.H., Carulli J.P., Chesi A., Chung W.K., Cirulli E.T., Cooper G.M., Couthouis J., Day-Williams A.G., Dion P.A., Gitler A.D., Glass J.D., Han Y., Harris T., Hayes S.D., Jones A.L., Keebler J., Krueger B.J., Lasseigne B.N., Levy S.E., Lu Y.-F., Maniatis T., McKenna-Yasek D., Myers R.M., Petrovski S., Pulst S.M., Raphael A.R., Ravits J.M., Ren Z., Rouleau G.A., Sapp P.C., Sims K.B., Staropoli J.F., Waite L.L., Wang Q., Wimbish J.R., Xin W.W., Phatnani H., Kwan J., Broach J., Arcila-Londono X., Lee E.B., Van Deerlin V.M., Fraenkel E., Ostrow L.W., Baas F., Zaitlen N., Berry J.D., Malaspina A., Fratta P., Cox G.A., Thompson L.M., Finkbeiner S., Dardiotis E., Hornstein E., MacGowan D.J.L., Heiman-Patterson T., Hammell M.G., Patsopoulos N.A., Dubnau J., Nath A., Musunuri R.L., Evani U.S., Abhyankar A., Zody M.C., Kaye J., Wyman S.K., LeNail A., Lima L., Rothstein J.D., Svendsen C.N., Van Eyk J.E., Maragakis N.J., Kolb S.J., Cudkowicz M., Baxi E., Benatar M., Taylor J.P., Wu G., Rampersaud E., Wuu J., Rademakers R., Zuchner S., Schule R., McCauley J., Hussain S., Cooley A., Wallace M., Clayman C., Barohn R., Statland J., Swenson A., Jackson C., Trivedi J., Khan S., Katz J., Jenkins L., Burns T., Gwathmey K., Caress J., McMillan C., Elman L., Pioro E.P., Heckmann J., So Y., Walk D., Maiser S., Zhang J., Silani V., Gellera C., Ratti A., Taroni F., Lauria G., Verde F., Fogh I., Tiloca C., Comi G.P., Soraru G., Cereda C., De Marchi F., Corti S., Ceroni M., Siciliano G., Filosto M., Inghilleri M., Peverelli S., Colombrita C., Poletti B., Maderna L., Del Bo R., Gagliardi S., Querin G., Bertolin C., Pensato V., Castellotti B., Camu W., Mouzat K., Lumbroso S., Corcia P., Meininger V., Besson G., Lagrange E., Clavelou P., Guy N., Couratier P., Vourch P., Danel V., Bernard E., Lemasson G., Laaksovirta H., Myllykangas L., Jansson L., Valori M., Ealing J., Hamdalla H., Rollinson S., Pickering-Brown S., Orrell R.W., Sidle K.C., Hardy J., Singleton A.B., Johnson J.O., Arepalli S., Polak M., Asress S., Al-Sarraj S., King A., Troakes C., Vance C., de Belleroche J., ten Asbroek A.L.M.A., Munoz-Blanco J.L., Hernandez D.G., Ding J., Gibbs J.R., Scholz S.W., Floeter M.K., Campbell R.H., Landi F., Bowser R., Kirby J., Pamphlett R., Gerhard G., Dunckley T.L., Brady C.B., Kowall N.W., Troncoso J.C., Le Ber I., Heiman-Patterson T.D., Kamel F., Van Den Bosch L., Strom T.M., Meitinger T., Shatunov A., Van Eijk K.R., de Carvalho M., Kooyman M., Middelkoop B., Moisse M., McLaughlin R.L., Van Es M.A., Weber M., Boylan K.B., Van Blitterswijk M., Morrison K.E., Basak A.N., Mora J.S., Drory V.E., Shaw P.J., Turner M.R., Talbot K., Hardiman O., Williams K.L., Fifita J.A., Nicholson G.A., Blair I.P., Esteban-Perez J., Garcia-Redondo A., Al-Chalabi A., Al Kheifat A., Andersen P.M., Chio A., Cooper-Knock J., Dekker A., Redondo A.G., Gotkine M., Hide W., Iacoangeli A., Kiernan M., Landers J.E., Mill J., Neto M.M., Pardina J.M., Newhouse S., Pinto S., Pulit S., Robberecht W., Shaw C., Sproviero W., Tazelaar G., Van Damme P., van den Berg L.H., van Vugt J., Veldink J.H., Zatz M., Bauer D.C., Twine N.A., Rogaeva E., Zinman L., Brice A., Feldman E.L., Ludolph A.C., Weishaupt J.H., Trojanowski J.Q., Stone D.J., Tienari P., Shaw C.E., Traynor B.J., ITALSGEN Consortium, Genomic Translation ALS Care GTAC, ALS Sequencing Consortium, NYGC ALS Consortium, Answer ALS Fdn, Clinical Res ALS Related Disorders, SLAGEN Consortium, French ALS Consortium, Project MinE ALS Sequencing Consor, Medical Research Council (MRC), ANS - Complex Trait Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Università cattolica del Sacro Cuore [Roma] (Unicatt), Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier] (SLA CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1), Lunar and Planetary Laboratory [Tucson] (LPL), University of Arizona, Università degli studi di Torino (UNITO), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), New York Genome Center [New York], New York Genome Center, Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), St Jude Children's Research Hospital, Howard Hughes Medical Institute [Chevy Chase] (HHMI), Howard Hughes Medical Institute (HHMI), Centre de compétence de la Sclérose Latérale Amyotrophique [CHRU Tours] (SLA CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), University College of London [London] (UCL), Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), King‘s College London, University of New Haven [Connecticut], Princeton University, Laboratoire de Biochimie [CHRU Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Helmholtz-Zentrum München (HZM), University Medical Center [Utrecht], Deutsches Forschungszentrum für Künstliche Intelligenz GmbH = German Research Center for Artificial Intelligence (DFKI), Mayo Clinic [Jacksonville], Trinity College Dublin, Maurice Wohl Clinical Neuroscience Institut, Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Repositório da Universidade de Lisboa, Nicolas, A, Kenna, K, Renton, A, Ticozzi, N, Faghri, F, Chia, R, Dominov, J, Kenna, B, Nalls, M, Keagle, P, Rivera, A, van Rheenen, W, Murphy, N, van Vugt, J, Geiger, J, van der Spek, R, Pliner, H, Shankaracharya, N, Smith, B, Marangi, G, Topp, S, Abramzon, Y, Gkazi, A, Eicher, J, Kenna, A, Logullo, F, Simone, I, Logroscino, G, Salvi, F, Bartolomei, I, Borghero, G, Murru, M, Costantino, E, Pani, C, Puddu, R, Caredda, C, Piras, V, Tranquilli, S, Cuccu, S, Corongiu, D, Melis, M, Milia, A, Marrosu, F, Marrosu, M, Floris, G, Cannas, A, Capasso, M, Caponnetto, C, Mancardi, G, Origone, P, Mandich, P, Conforti, F, Cavallaro, S, Mora, G, Marinou, K, Sideri, R, Penco, S, Mosca, L, Lunetta, C, Pinter, G, Corbo, M, Riva, N, Carrera, P, Volanti, P, Mandrioli, J, Fini, N, Fasano, A, Tremolizzo, L, Arosio, A, Ferrarese, C, Trojsi, F, Tedeschi, G, Monsurrò, M, Piccirillo, G, Femiano, C, Ticca, A, Ortu, E, La Bella, V, Spataro, R, Colletti, T, Sabatelli, M, Zollino, M, Conte, A, Luigetti, M, Lattante, S, Santarelli, M, Petrucci, A, Pugliatti, M, Pirisi, A, Parish, L, Occhineri, P, Giannini, F, Battistini, S, Ricci, C, Benigni, M, Cau, T, Loi, D, Calvo, A, Moglia, C, Brunetti, M, Barberis, M, Restagno, G, Casale, F, Marrali, G, Fuda, G, Ossola, I, Cammarosano, S, Canosa, A, Ilardi, A, Manera, U, Grassano, M, Tanel, R, Pisano, F, Mazzini, L, Messina, S, D'Alfonso, S, Corrado, L, Ferrucci, L, Harms, M, Goldstein, D, Shneider, N, Goutman, S, Simmons, Z, Miller, T, Chandran, S, Pal, S, Manousakis, G, Appel, S, Simpson, E, Wang, L, Baloh, R, Gibson, S, Bedlack, R, Lacomis, D, Sareen, D, Sherman, A, Bruijn, L, Penny, M, Moreno, C, Kamalakaran, S, Allen, A, Boone, B, Brown, R, Carulli, J, Chesi, A, Chung, W, Cirulli, E, Cooper, G, Couthouis, J, Day-Williams, A, Dion, P, Gitler, A, Glass, J, Han, Y, Harris, T, Hayes, S, Jones, A, Keebler, J, Krueger, B, Lasseigne, B, Levy, S, Lu, Y, Maniatis, T, McKenna-Yasek, D, Myers, R, Petrovski, S, Pulst, S, Raphael, A, Ravits, J, Ren, Z, Rouleau, G, Sapp, P, Sims, K, Staropoli, J, Waite, L, Wang, Q, Wimbish, J, Xin, W, Phatnani, H, Kwan, J, Broach, J, Arcila-Londono, X, Lee, E, Van Deerlin, V, Fraenkel, E, Ostrow, L, Baas, F, Zaitlen, N, Berry, J, Malaspina, A, Fratta, P, Cox, G, Thompson, L, Finkbeiner, S, Dardiotis, E, Hornstein, E, Macgowan, D, Heiman-Patterson, T, Hammell, M, Patsopoulos, N, Dubnau, J, Nath, A, Musunuri, R, Evani, U, Abhyankar, A, Zody, M, Kaye, J, Wyman, S, Lenail, A, Lima, L, Rothstein, J, Svendsen, C, Van Eyk, J, Maragakis, N, Kolb, S, Cudkowicz, M, Baxi, E, Benatar, M, Taylor, J, Wu, G, Rampersaud, E, Wuu, J, Rademakers, R, Züchner, S, Schule, R, Mccauley, J, Hussain, S, Cooley, A, Wallace, M, Clayman, C, Barohn, R, Statland, J, Swenson, A, Jackson, C, Trivedi, J, Khan, S, Katz, J, Jenkins, L, Burns, T, Gwathmey, K, Caress, J, Mcmillan, C, Elman, L, Pioro, E, Heckmann, J, So, Y, Walk, D, Maiser, S, Zhang, J, Silani, V, Gellera, C, Ratti, A, Taroni, F, Lauria, G, Verde, F, Fogh, I, Tiloca, C, Comi, G, Sorarù, G, Cereda, C, De Marchi, F, Corti, S, Ceroni, M, Siciliano, G, Filosto, M, Inghilleri, M, Peverelli, S, Colombrita, C, Poletti, B, Maderna, L, Del Bo, R, Gagliardi, S, Querin, G, Bertolin, C, Pensato, V, Castellotti, B, Camu, W, Mouzat, K, Lumbroso, S, Corcia, P, Meininger, V, Besson, G, Lagrange, E, Clavelou, P, Guy, N, Couratier, P, Vourch, P, Danel, V, Bernard, E, Lemasson, G, Laaksovirta, H, Myllykangas, L, Jansson, L, Valori, M, Ealing, J, Hamdalla, H, Rollinson, S, Pickering-Brown, S, Orrell, R, Sidle, K, Hardy, J, Singleton, A, Johnson, J, Arepalli, S, Polak, M, Asress, S, Al-Sarraj, S, King, A, Troakes, C, Vance, C, de Belleroche, J, ten Asbroek, A, Muñoz-Blanco, J, Hernandez, D, Ding, J, Gibbs, J, Scholz, S, Floeter, M, Campbell, R, Landi, F, Bowser, R, Kirby, J, Pamphlett, R, Gerhard, G, Dunckley, T, Brady, C, Kowall, N, Troncoso, J, Le Ber, I, Kamel, F, Van Den Bosch, L, Strom, T, Meitinger, T, Shatunov, A, Van Eijk, K, de Carvalho, M, Kooyman, M, Middelkoop, B, Moisse, M, Mclaughlin, R, Van Es, M, Weber, M, Boylan, K, Van Blitterswijk, M, Morrison, K, Basak, A, Mora, J, Drory, V, Shaw, P, Turner, M, Talbot, K, Hardiman, O, Williams, K, Fifita, J, Nicholson, G, Blair, I, Esteban-Pérez, J, García-Redondo, A, Al-Chalabi, A, Al Kheifat, A, Andersen, P, Chio, A, Cooper-Knock, J, Dekker, A, Redondo, A, Gotkine, M, Hide, W, Iacoangeli, A, Kiernan, M, Landers, J, Mill, J, Neto, M, Pardina, J, Newhouse, S, Pinto, S, Pulit, S, Robberecht, W, Shaw, C, Sproviero, W, Tazelaar, G, van Damme, P, van den Berg, L, van Eijk, K, van Es, M, Veldink, J, Zatz, M, Bauer, D, Twine, N, Rogaeva, E, Zinman, L, Brice, A, Feldman, E, Ludolph, A, Weishaupt, J, Trojanowski, J, Stone, D, Tienari, P, Chiò, A, Traynor, B, Nicolas, Aude, Kenna, Kevin P, Renton, Alan E, Ticozzi, Nicola, Faghri, Faraz, Chia, Ruth, Dominov, Janice A, Kenna, Brendan J, Nalls, Mike A, Keagle, Pamela, Rivera, Alberto M, van Rheenen, Wouter, Murphy, Natalie A, van Vugt, Joke J F A, Geiger, Joshua T, Van der Spek, Rick A, Pliner, Hannah A, Shankaracharya, Null, Smith, Bradley N, Marangi, Giuseppe, Topp, Simon D, Abramzon, Yevgeniya, Gkazi, Athina Soragia, Eicher, John D, Kenna, Aoife, Mora, Gabriele, Calvo, Andrea, Mazzini, Letizia, Riva, Nilo, Mandrioli, Jessica, Caponnetto, Claudia, Battistini, Stefania, Volanti, Paolo, La Bella, Vincenzo, Conforti, Francesca L, Borghero, Giuseppe, Messina, Sonia, Simone, Isabella L, Trojsi, Francesca, Salvi, Fabrizio, Logullo, Francesco O, D'Alfonso, Sandra, Corrado, Lucia, Capasso, Margherita, Ferrucci, Luigi, Logullo, Fo, Murru, Mr, Marrosu, Mg, Conforti, Fl, Pinter, Gl, Tedeschi, Gioacchino, Monsurrò, Maria Rosaria, Parish, Ld, Cau, Tb, Moreno, Cristiane de Araujo Martin, Kamalakaran, Sitharthan, Goldstein, David B, Gitler, Aaron D, Harris, Tim, Myers, Richard M, Phatnani, Hemali, Musunuri, Rajeeva Lochan, Evani, Uday Shankar, Abhyankar, Avinash, Zody, Michael C, Kaye, Julia, Finkbeiner, Steven, Wyman, Stacia K, Lenail, Alex, Lima, Leandro, Fraenkel, Ernest, Svendsen, Clive N, Thompson, Leslie M, Van Eyk, Jennifer E, Berry, James D, Miller, Timothy M, Kolb, Stephen J, Cudkowicz, Merit, Baxi, Emily, Benatar, Michael, Taylor, J Paul, Rampersaud, Evadnie, Wu, Gang, Wuu, Joanne, Lauria, Giuseppe, Verde, Federico, Fogh, Isabella, Tiloca, Cinzia, Comi, Giacomo P, Sorarù, Gianni, Cereda, Cristina, Corcia, Philippe, Laaksovirta, Hannu, Myllykangas, Liisa, Jansson, Lilja, Valori, Miko, Ealing, John, Hamdalla, Hisham, Rollinson, Sara, Pickering-Brown, Stuart, Orrell, Richard W, Sidle, Katie C, Malaspina, Andrea, Hardy, John, Singleton, Andrew B, Johnson, Janel O, Arepalli, Sampath, Sapp, Peter C, McKenna-Yasek, Diane, Polak, Meraida, Asress, Seneshaw, Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Vance, Caroline, de Belleroche, Jacqueline, Baas, Frank, Ten Asbroek, Anneloor L M A, Muñoz-Blanco, José Lui, Hernandez, Dena G, Ding, Jinhui, Gibbs, J Raphael, Scholz, Sonja W, Floeter, Mary Kay, Campbell, Roy H, Landi, Francesco, Bowser, Robert, Pulst, Stefan M, Ravits, John M, Macgowan, Daniel J L, Kirby, Janine, Pioro, Erik P, Pamphlett, Roger, Broach, Jame, Gerhard, Glenn, Dunckley, Travis L, Brady, Christopher B, Kowall, Neil W, Troncoso, Juan C, Le Ber, Isabelle, Mouzat, Kevin, Lumbroso, Serge, Heiman-Patterson, Terry D, Kamel, Freya, Van Den Bosch, Ludo, Baloh, Robert H, Strom, Tim M, Meitinger, Thoma, Shatunov, Aleksey, Van Eijk, Kristel R, de Carvalho, Mamede, Kooyman, Maarten, Middelkoop, Ba, Moisse, Matthieu, Mclaughlin, Russell L, Van Es, Michael A, Weber, Marku, Boylan, Kevin B, Van Blitterswijk, Marka, Rademakers, Rosa, Morrison, Karen E, Basak, A Nazli, Mora, Jesús S, Drory, Vivian E, Shaw, Pamela J, Turner, Martin R, Talbot, Kevin, Hardiman, Orla, Williams, Kelly L, Fifita, Jennifer A, Nicholson, Garth A, Blair, Ian P, Rouleau, Guy A, Esteban-Pérez, Jesú, García-Redondo, Alberto, Al-Chalabi, Ammar, Rogaeva, Ekaterina, Zinman, Lorne, Ostrow, Lyle W, Maragakis, Nicholas J, Rothstein, Jeffrey D, Simmons, Zachary, Cooper-Knock, Johnathan, Brice, Alexi, Goutman, Stephen A, Feldman, Eva L, Gibson, Summer B, Taroni, Franco, Ratti, Antonia, Gellera, Cinzia, Van Damme, Philip, Robberecht, Wim, Fratta, Pietro, Sabatelli, Mario, Lunetta, Christian, Ludolph, Albert C, Andersen, Peter M, Weishaupt, Jochen H, Camu, William, Trojanowski, John Q, Van Deerlin, Vivianna M, Brown, Robert H, van den Berg, Leonard H, Veldink, Jan H, Harms, Matthew B, Glass, Jonathan D, Stone, David J, Tienari, Pentti, Silani, Vincenzo, Chiò, Adriano, Shaw, Christopher E, Traynor, Bryan J, Landers, John E, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
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Male ,Als gene ,Genome-wide association study ,FAMILIAL ALS ,ALS ,axonal transport ,cargo ,GWAS ,KIF5A ,WES ,WGS ,0302 clinical medicine ,80 and over ,Psychology ,Aetiology ,Aged, 80 and over ,0303 health sciences ,French ALS Consortium ,Kinesin ,KINESIN HEAVY-CHAIN ,Cognitive Sciences ,Human ,Hereditary spastic paraplegia ,Neuroscience(all) ,Single-nucleotide polymorphism ,TARGETED DISRUPTION ,Article ,03 medical and health sciences ,Genetics ,Humans ,Amino Acid Sequence ,Loss function ,Aged ,HEXANUCLEOTIDE REPEAT ,Neuroscience (all) ,MUTATIONS ,Amyotrophic Lateral Sclerosis ,3112 Neurosciences ,1702 Cognitive Science ,medicine.disease ,ITALSGEN Consortium ,Answer ALS Foundation ,030104 developmental biology ,ALS Sequencing Consortium ,Human medicine ,1109 Neurosciences ,030217 neurology & neurosurgery ,0301 basic medicine ,[SDV]Life Sciences [q-bio] ,Kinesins ,Neurodegenerative ,Genetic analysis ,Genome ,AMYOTROPHIC-LATERAL-SCLEROSIS ,3124 Neurology and psychiatry ,Cohort Studies ,Pathogenesis ,Loss of Function Mutation ,Missense mutation ,2.1 Biological and endogenous factors ,Amyotrophic lateral sclerosis ,NYGC ALS Consortium ,General Neuroscience ,ALS, axonal transport, cargo, GWAS, KIF5A, WES, WGS ,Middle Aged ,Phenotype ,Settore MED/26 - NEUROLOGIA ,Neurological ,Project MinE ALS Sequencing Consortium ,Female ,Adult ,Biology ,GENOTYPE IMPUTATION ,Genome-Wide Association Study ,Young Adult ,NO ,Rare Diseases ,medicine ,SLAGEN Consortium ,Gene ,030304 developmental biology ,Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium ,Neurology & Neurosurgery ,Human Genome ,Neurosciences ,AXONAL-TRANSPORT ,Brain Disorders ,Family member ,DNA-DAMAGE ,MOTOR-NEURONS ,3111 Biomedicine ,Cohort Studie ,Genomic Translation for ALS Care (GTAC) Consortium ,Amyotrophic Lateral Sclerosi - Abstract
© 2018 Elsevier Inc., To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
- Published
- 2018
32. Targeted Genetic Screen in Amyotrophic Lateral Sclerosis Reveals Novel Genetic Variants with Synergistic Effect on Clinical Phenotype
- Author
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Johnathan Cooper-Knock, Henry Robins, Isabell Niedermoser, Matthew Wyles, Paul R. Heath, Adrian Higginbottom, Theresa Walsh, Mbombe Kazoka, Project MinE ALS Sequencing Consortium, Paul G. Ince, Guillaume M. Hautbergue, Christopher J. McDermott, Janine Kirby, Pamela J. Shaw, Ahmad Al Kheifat, Ammar Al-Chalabi, Nazli Basak, Ian Blair, Annelot Dekker, Orla Hardiman, Winston Hide, Alfredo Iacoangeli, Kevin Kenna, John Landers, Russel McLaughlin, Jonathan Mill, Bas Middelkoop, Mattieu Moisse, Jesus Mora Pardina, Karen Morrison, Stephen Newhouse, Sara Pulit, Aleksey Shatunov, Chris Shaw, William Sproviero, Gijs Tazelaar, Philip van Damme, Leonard van den Berg, Rick van der Spek, Kristelvan Eijk, Michael van Es, Wouter van Rheenen, Joke van Vugt, Jan Veldink, Maarten Kooyman, Jonathan Glass, Wim Robberecht, Marc Gotkine, Vivian Drory, Matthew Kiernan, Miguel Mitne Neto, Mayana Ztaz, Philippe Couratier, Philippe Corcia, Vincenzo Silani, Adriano Chio, Mamede de Carvalho, Susana Pinto, Alberto Garcia Redondo, Peter Andersen, Markus Weber, and Nicola Ticozzi
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amyotrophic lateral sclerosis ,C9ORF72 ,oligogenic inheritance ,RNA binding proteins ,DNA sequencing ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,lcsh:RC321-571 - Abstract
Amyotrophic lateral sclerosis (ALS) is underpinned by an oligogenic rare variant architecture. Identified genetic variants of ALS include RNA-binding proteins containing prion-like domains (PrLDs). We hypothesized that screening genes encoding additional similar proteins will yield novel genetic causes of ALS. The most common genetic variant of ALS patients is a G4C2-repeat expansion within C9ORF72. We have shown that G4C2-repeat RNA sequesters RNA-binding proteins. A logical consequence of this is that loss-of-function mutations in G4C2-binding partners might contribute to ALS pathogenesis independently of and/or synergistically with C9ORF72 expansions. Targeted sequencing of genomic DNA encoding either RNA-binding proteins or known ALS genes (n = 274 genes) was performed in ALS patients to identify rare deleterious genetic variants and explore genotype-phenotype relationships. Genomic DNA was extracted from 103 ALS patients including 42 familial ALS patients and 61 young-onset (average age of onset 41 years) sporadic ALS patients; patients were chosen to maximize the probability of identifying genetic causes of ALS. Thirteen patients carried a G4C2-repeat expansion of C9ORF72. We identified 42 patients with rare deleterious variants; 6 patients carried more than one variant. Twelve mutations were discovered in known ALS genes which served as a validation of our strategy. Rare deleterious variants in RNA-binding proteins were significantly enriched in ALS patients compared to control frequencies (p = 5.31E-18). Nineteen patients featured at least one variant in a RNA-binding protein containing a PrLD. The number of variants per patient correlated with rate of disease progression (t-test, p = 0.033). We identified eighteen patients with a single variant in a G4C2-repeat binding protein. Patients with a G4C2-binding protein variant in combination with a C9ORF72 expansion had a significantly faster disease course (t-test, p = 0.025). Our data are consistent with an oligogenic model of ALS. We provide evidence for a number of entirely novel genetic variants of ALS caused by mutations in RNA-binding proteins. Moreover we show that these mutations act synergistically with each other and with C9ORF72 expansions to modify the clinical phenotype of ALS. A key finding is that this synergy is present only between functionally interacting variants. This work has significant implications for ALS therapy development.
- Published
- 2017
33. Stem cells for amyotrophic lateral sclerosis modeling and therapy: Myth or fact?
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Oswaldo Keith Okamoto, Mayana Zatz, Giuliana Castello Coatti, M. S. Beccari, Miguel Mitne-Neto, and Thiago Rosa Olávio
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Histology ,business.industry ,Mesenchymal stem cell ,Cell Biology ,medicine.disease ,Embryonic stem cell ,Neural stem cell ,Pathology and Forensic Medicine ,Cell therapy ,Transplantation ,Medicine ,Stem cell ,Amyotrophic lateral sclerosis ,Induced pluripotent stem cell ,business ,Neuroscience - Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease whose pathophysiology is poorly understood. Aiming to better understand the cause of motor neuron death, the use of experimental cell-based models increased significantly over the past years. In this scenario, much knowledge has been generated from the study of motor neurons derived from embryonic stem cells and induced pluripotent stem cells. These methods, however, have advantages and disadvantages, which must be balanced on experimental design. Preclinical studies provide valuable information, making it possible to combine diverse methods to build an expanded knowledge of ALS pathophysiology. In addition to using stem cells as experimental models for understanding disease mechanism, these cells had been quoted for therapy in ALS. Despite ethical issues involved in its use, cell therapy with neural stem cells stands out. A phase I clinical trial was recently completed and a phase II is on its way, attesting the method's safety. In another approach, mesenchymal stromal cells capable of releasing neuroregulatory and anti-inflammatory factors have also been listed as candidates for cell therapy for ALS, and have been admitted as safe in a phase I trial. Despite recent advances, application of stem cells as an actual therapy for ALS patients is still in debate. Here, we discuss how stem cells have been useful in modeling ALS and address critical topics concerning their therapeutic use, such as administration protocols, injection site, cell type to be administered, type of transplantation (autologous vs. allogeneic) among other issues with particular implications for ALS therapy.
- Published
- 2015
34. Performance and validation of a tumor mutation profiling, based on artificial intelligence annotation, to assist oncology decision making
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Matheus Carvalho Bürger, Maria Carolina Pintão, Gabriela Rampazzo Valim, Andre Yuji Oku, Ilka Lopes Santoro, Miguel Mitne Neto, Luciana Guilhermino Pereira, Monica Maria Agata Stiepcich, Otavio Jose Eulalio, Luciana Peniche Moreira, Raquel Stabellini, Elisa Napolitano Ferreira, Aloisio Souza Felipe-Silva, Rodrigo Fernandes Ramalho, Gisele W. B. Colleoni, Alexandre Ricardo dos Santos Fornari, David Santos Marco Antonio, and Ana Maria Fraga
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Cancer Research ,Annotation ,Mutation profiling ,Oncology ,business.industry ,Component (UML) ,Key (cryptography) ,Medicine ,Orienteering ,Identification (biology) ,Computational biology ,business - Abstract
e13148 Background: Tumor mutation profiling has become a key component for orienteering the treatment of oncologic patients. A crucial step for this is the correct identification and classification of pathogenic and actionable variants. In the present work we aimed at the development and validation of a tumor mutation profiling panel, based on NGS, which uses artificial intelligence for variant annotation. Methods: We designed a hybrid capture panel, containing 366 genes to evaluate somatic SNVs, INDELs and CNVs, and to calculate TMB, using a customized bioinformatics pipeline. MSI status was determined by fragment analysis using capillary electrophoresis. Analytical performance was determined using reference cell lines. FFPE samples from 70 tumors were accessed and 53 were sequenced. Variant annotation was performed by IBM Watson for Genomics (WfG) platform. Assay performance on clinical samples was defined based on orthogonal assays using Agilent CGH+SNParray 400K (for CNVs only) and Foundation One test (Foundation Medicine) (F1). Results: Breast, colon and lung were the most common tumor origins. Fifty-three samples were successfully sequenced, while 41 of them could also be analyzed by F1 test. A summary of the assay performance is presented in Table 1. Our pipeline detected 1219 variants and 290 (23%) were classified as Pathogenic, Likely Pathogenic or Actionable, according to WfG. Thirty-five samples (66%) presented a variant that could drive the treatment, with 37.7% of samples being sensitive to targeted therapies, while 22.6% were resistant; additionally, 86% had an indication for a clinical trial. Conclusions: The developed assay presented a good overall sensitivity and allele frequency correlation, with TMB and MSI having the best rates. Comparisons with F1 had reduced values of concordance; however, SNVs and INDELs presented a similar frequency. Differences on CNVs identification may rely on distinct thresholds established by the different groups. The high percentage of samples that could benefit from mutational profiling highlights the importance of such approach in the clinical routine. Additionally, the high number of variants features the need for updated information for annotation. [Table: see text]
- Published
- 2019
35. A novel GNRHR gene mutation causing congenital hypogonadotrophic hypogonadism in a Brazilian kindred
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Eugenia Verônica Hernandez Orchard, Marina M. L. Kizys, Silvia R. Correa-Silva, Rafael Filipelli, Magnus R. Dias-da-Silva, David Santos Marco Antonio, Jessica da Silva Fausto, Flávia A. Costa-Barbosa, Miguel Mitne-Neto, Andre Yuji Oku, and Gilberto K. Furuzawa
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Male ,0301 basic medicine ,Proband ,medicine.medical_specialty ,Inositol Phosphates ,Endocrinology, Diabetes and Metabolism ,030209 endocrinology & metabolism ,Gene mutation ,Biology ,medicine.disease_cause ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Endocrinology ,Internal medicine ,Exome Sequencing ,medicine ,Humans ,Genetic Predisposition to Disease ,Exome ,Cells, Cultured ,Exome sequencing ,Genetics ,Mutation ,Massive parallel sequencing ,Endocrine and Autonomic Systems ,Hypogonadism ,GNRHR ,Pedigree ,030104 developmental biology ,Female ,Brazil ,Receptors, LHRH ,Hypogonadotrophic hypogonadism - Abstract
Congenital hypogonadotrophic hypogonadism (CHH) is a challenging inherited endocrine disorder characterised by absent or incomplete pubertal development and infertility as a result of the low action/secretion of the hypothalamic gonadotrophin-releasing hormone (GnRH). Given a growing list of gene mutations accounting for CHH, the application of massively parallel sequencing comprises an excellent molecular diagnostic approach because it enables the simultaneous evaluation of many genes. The present study proposes the use of whole exome sequencing (WES) to identify causative and modifying mutations based on a phenotype-genotype CHH analysis using an in-house exome pipeline. Based on 44 known genes related to CHH in humans, we were able to identify a novel homozygous gonadotrophin-releasing hormone receptor (GNRHR) p.Thr269Met mutant, which segregates with the CHH kindred and was predicted to be deleterious by in silico analysis. A functional study measuring intracellular inositol phosphate (IP) when stimulated with GnRH on COS-7 cells confirmed that the p.Thr269Met GnRHR mutant performed greatly diminished IP accumulation relative to the transfected wild-type GnRHR. Additionally, the proband carries three heterozygous variants in CCDC141 and one homozygous in SEMA3A gene, although their effects with respect to modifying the phenotype are uncertain. Because they do not segregate with reproductive phenotype in family members, we advocate they do not contribute to CHH oligogenicity. WES proved to be useful for CHH molecular diagnosis and reinforced its benefit with respect to identifying heterogeneous genetic disorders. Our findings expand the GnRHR mutation spectrum and phenotype-genotype correlation in CHH.
- Published
- 2018
36. Different Donors Mesenchymal Stromal Cells Secretomes Reveal Heterogeneous Profile of Relevance for Therapeutic Use
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Giuliana Castello Coatti, Miguel Mitne-Neto, M. Valadares, Mayra Pelatti, A. Assoni, Melinda Beccari, Mayana Zatz, Valdemir Melechco Carvalho, and J. Gomes
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0301 basic medicine ,Proteome ,Duchenne muscular dystrophy ,Adipose tissue ,Apoptosis ,Mesenchymal Stem Cell Transplantation ,Cell Line ,Myoblasts ,03 medical and health sciences ,Cell Movement ,medicine ,Myocyte ,Humans ,Protein metabolic process ,biology ,Mesenchymal stem cell ,Skeletal muscle ,Mesenchymal Stem Cells ,Cell Biology ,Hematology ,medicine.disease ,Coculture Techniques ,Tissue Donors ,Muscular Dystrophy, Duchenne ,030104 developmental biology ,medicine.anatomical_structure ,Cytoprotection ,Culture Media, Conditioned ,Immunology ,biology.protein ,Cancer research ,Female ,Stem cell ,Dystrophin ,Developmental Biology - Abstract
Duchenne muscular dystrophy (DMD) is a lethal X-linked disorder caused by null mutations in the dystrophin gene. Although the primary defect is the deficiency of muscle dystrophin, secondary events, including chronic inflammation, fibrosis, and muscle regeneration failure are thought to actively contribute to disease progression. Despite several advances, there is still no effective therapy for DMD. Therefore, the potential regenerative capacities, and immune-privileged properties of mesenchymal stromal cells (MSCs), have been the focus of intense investigation in different animal models aiming the treatment of these disorders. However, these studies have shown different outcomes according to the sources from which MSCs were obtained, which raise the question whether stem cells from distinct sources have comparable clinical effects. Here, we analyzed the protein content of the secretome of MSCs, isolated from three different sources (adipose tissue, skeletal muscle, and uterine tubes), obtained from five donors and evaluated their in vitro properties when cocultured with DMD myoblasts. All MSC lineages showed pathways enrichment related to protein metabolic process, oxidation-reduction process, cell proliferation, and regulation of apoptosis. We found that MSCs secretome proteins and their effect in vitro vary significantly according to the tissue and donors, including opposite effects in apoptosis assay, indicating the importance of characterizing MSC secretome profile before its use in animal and clinical trials. Despite the individual differences a pool of conditioned media from all MSCs lineages was able to delay apoptosis and enhance migration when in contact with DMD myoblasts.
- Published
- 2016
37. Downregulation of VAPB expression in motor neurons derived from induced pluripotent stem cells of ALS8 patients
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Mayana Zatz, Claudio A. P. Joazeiro, Alysson R. Muotri, Maria C. Marchetto, Mario H. Bengtson, Miguel Mitne-Neto, Hugo J. Bellen, Marcela Camara Machado-Costa, Monize Lazar, Acary Souza Bulle Oliveira, Hiroshi Tsuda, Helga Cristina Almeida da Silva, Univ Calif San Diego, Universidade de São Paulo (USP), Universidade Federal de São Paulo (UNIFESP), Salk Inst Biol Studies, Scripps Res Inst, and Baylor Coll Med
- Subjects
Male ,Neuromuscular disease ,Cellular differentiation ,Induced Pluripotent Stem Cells ,Vesicular Transport Proteins ,Down-Regulation ,Biology ,medicine.disease_cause ,Pathogenesis ,Downregulation and upregulation ,Genetics ,medicine ,Humans ,Amyotrophic lateral sclerosis ,Induced pluripotent stem cell ,Molecular Biology ,Genetics (clinical) ,Cells, Cultured ,Motor Neurons ,Mutation ,CÉLULAS-TRONCO ,Amyotrophic Lateral Sclerosis ,Cell Differentiation ,General Medicine ,Articles ,VAPB ,Fibroblasts ,medicine.disease ,Cell biology ,Pedigree ,Female - Abstract
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Instituto Nacional de celulas-tronco em doencas geneticas (INCT) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Muscular Dystrophy Association Instituto Paulo Gontijo (IPG) Amyotrophic lateral sclerosis (ALS) is an incurable neuromuscular disease that leads to a profound loss of life quality and premature death. Around 10% of the cases are inherited and ALS8 is an autosomal dominant form of familial ALS caused by mutations in the vamp-associated protein B/C (VAPB) gene. the VAPB protein is involved in many cellular processes and it likely contributes to the pathogenesis of other forms of ALS besides ALS8. A number of successful drug tests in ALS animal models could not be translated to humans underscoring the need for novel approaches. the induced pluripotent stem cells (iPSC) technology brings new hope, since it can be used to model and investigate diseases in vitro. Here we present an additional tool to study ALS based on ALS8-iPSC. Fibroblasts from ALS8 patients and their non-carrier siblings were successfully reprogrammed to a pluripotent state and differentiated into motor neurons. We show for the first time that VAPB protein levels are reduced in ALS8-derived motor neurons but, in contrast to over-expression systems, cytoplasmic aggregates could not be identified. Our results suggest that optimal levels of VAPB may play a central role in the pathogenesis of ALS8, in agreement with the observed reduction of VAPB in sporadic ALS. Univ Calif San Diego, Rady Childrens Hosp San Diego, Dept Cellular & Mol Med, Sch Med,Dept Pediat,Stem Cell Program, La Jolla, CA 92093 USA Univ São Paulo, Human Genome Res Ctr, Dept Genet & Evolut Biol, BR-05508090 São Paulo, Brazil Universidade Federal de São Paulo, Paulista Sch Med, São Paulo, Brazil Salk Inst Biol Studies, Genet Lab, La Jolla, CA 92037 USA Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA Baylor Coll Med, Dept Mol & Human Genet, Jan & Dan Duncan Neurol Res Inst, Houston, TX 77030 USA Baylor Coll Med, Program Dev Biol, Jan & Dan Duncan Neurol Res Inst, Houston, TX 77030 USA Universidade Federal de São Paulo, Paulista Sch Med, São Paulo, Brazil Muscular Dystrophy Association: MDA185410 Web of Science
- Published
- 2011
38. CALR mutations screening in wild type 'JAK2 POT. V617F´ and 'MPL POT. W515K/L´ Brazilian myeloproliferative neoplasm patients
- Author
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Marcelo Gil Cliquet, Daniela Prudente Teixeira Nunes, Marcos Tadeu dos Santos, Luciene Terezina Lima, Elvira Maria Guerra-Shinohara, Maria de Lourdes Lopes Ferrari Chauffaille, and Miguel Mitne-Neto
- Subjects
medicine.medical_specialty ,Pathology ,Mutant ,medicine.disease_cause ,Real-Time Polymerase Chain Reaction ,Gastroenterology ,symbols.namesake ,Mutation Rate ,Internal medicine ,medicine ,Humans ,Jak2v617f mutation ,Myelofibrosis ,Molecular Biology ,Myeloproliferative neoplasm ,LEUCEMIA MIELOIDE ,Sanger sequencing ,Mutation ,Myeloproliferative Disorders ,business.industry ,Essential thrombocythemia ,Platelet Count ,Wild type ,Cell Biology ,Hematology ,Janus Kinase 2 ,medicine.disease ,Thrombopoietin ,symbols ,Molecular Medicine ,business ,Calreticulin ,Brazil - Abstract
Some myeloproliferative neoplasm (MPN) patients harbor JAK2(V617F) mutation, and CALR mutations were recently discovered in wild type (WT) JAK2(V617F). We evaluated the frequency and type of CALR mutations, and clinical and hematological characteristics in WT JAK2(V617F) and MPL(W515K/L) MPN patients. Sixty-five patients were included: 21 with primary myelofibrosis (PMF), 21 with myelofibrosis post-essential thrombocythemia (MPET) and 23 with essential thrombocythemia (ET). Screening for JAK2(V617F) and MPL(W515K/L) were performed using real-time PCR, while CALR mutations were analyzed by fragment analysis and Sanger sequencing. JAK2(V617F) was the most frequent mutation (54.5%) and one patient (1.5%) harbored MPL(W515L). CALR mutations were present in 38.1% of PMF, 12.5% of ET and 33.3% of MPET patients. Five types of CALR mutations were detected, among which type 1 (32.1%) and type 2 (21.4%) were found to be the most common. A novel CALR mutation in a PMF patient was found. Patients carrying CALR mutations had higher platelet count and less presence of splenomegaly than JAK2(V617F), while triple negatives had higher C-reactive protein levels than CALR mutant carriers. Screening for CALR mutations and its correlation with clinical features could be useful for the characterization of MPN patients and result in its incorporation into a new prognostic score.
- Published
- 2015
39. Induced Pluripotent Stem Cells and Amyotrophic Lateral Sclerosis
- Author
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Miguel Mitne-Neto
- Subjects
New horizons ,Human disease ,business.industry ,Basic research ,Cell autonomous ,Genetic model ,Medicine ,Disease ,Amyotrophic lateral sclerosis ,Induced pluripotent stem cell ,business ,medicine.disease ,Neuroscience - Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal and incurable disease that affects 1–2 in 100,000 individuals. Despite of the extensive efforts in basic research and the use of different animal models in preclinical studies, most of the evaluated compounds and therapies tested in the last 30 years could not be translated to humans. The advent of induced pluripotent stem cells (iPSCs) technology allowed the generation of models that are more similar to the human disease scenario, turning the patient-in-a-dish into a reality. The present document aims to summarize some of the main aspects in the new field of modeling ALS using iPSC and their further application. The distinct genetic models, the challenges and advantages of iPSC for ALS studies, their application for cell autonomous and non-cell autonomous hypothesis, the search for new compounds, and the application of such technology for therapy are some the discussed aspects. The use of iPS cells for ALS research will certainly open new horizons and bring important data in order to find new therapies for this devastating disease.
- Published
- 2015
40. Method for definition of CIS-TRANS status in double CEBPA mutations
- Author
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Miguel Mitne-Neto, Caroline Monaco Moreira, and Ana Maria Fraga
- Subjects
Cancer Research ,Haematopoiesis ,medicine.anatomical_structure ,Oncology ,business.industry ,CEBPA ,Cancer research ,Medicine ,Myeloid leukemia ,Bone marrow ,business ,medicine.disease ,Infiltration (medical) - Abstract
e18511 Background: Acute myeloid leukemia (AML) is characterized by infiltration of blood and bone marrow by proliferative, clonal and abnormally differentiated hematopoietic cells, affecting 3 in 100.000 adults. CEBPA is a transcription factor and a biomarker for cytogenetically normal (CN) patients. Somatic CEBPA mutations occur in 10% of CN patients and recent studies have shown that a favorable outcome may only be obtained in those carrying CEBPA mutations in different alleles ( trans). The evaluation of double mutations and the definition of bi-allelic ( trans) versus mono-allelic ( cis) status applies long protocols, involving gene cloning and sequencing, which are challenging for the diagnostic routine and negatively impacts the turnaround time (TAT). The present study aimed the development of an alternate method for the identification of double mutations in CEBPA and its CIS- TRANScondition. Methods: A previously screened sample carrying double CEBPA mutations was selected and its DNA was extracted. This sample and a DNA control were quantified and diluted in order to obtain ½ DNA molecule per well for amplification, using digital PCR rationale. Samples were distributed in 40 wells of a 96 well plate. A pair of primers was used to amplify the entire CEBPA coding region in a Real-Time PCR using SYBR green-based detection in QuantStudio System. A subset of primers was used to amplify and to sequence the regions of interest. The entire process was repeated three times, in order to prove its reproducibility. Results: The above described dilution allowed an estimation that half of the wells had no DNA and half contained a single DNA molecule. An average of 18 wells presented amplification. Five of the positive wells were used as templates for a nested PCR followed by Sanger sequencing analysis. Since each mutation was identified as the result of distinct well amplification, we concluded that the mutations were in trans. Conclusions: Our results show that it is possible to determine the CIS- TRANS allelic configuration of CEBPA dual-mutation in a cost-effective process and with a short TAT, avoiding gene cloning systems. Additionally, the process is reproducible, can be easily implemented as a routine analysis and has a great impact for AML patients’ diagnosis.
- Published
- 2017
41. Complete Genome Sequence of an F8-Like Lytic Myovirus (φSPM-1) That Infects Metallo-β-Lactamase-Producing Pseudomonas aeruginosa
- Author
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Carlos Emílio Levy, Maria Inês Zanoli Sato, John A. McCulloch, Nilton Lincopan, Louise Cerdeira, Patrícia R. Neves, Miguel Mitne-Neto, Jorge Luiz Mello Sampaio, Theo G M Oliveira, and Elsa Masae Mamizuka
- Subjects
Whole genome sequencing ,food.ingredient ,Pseudomonas aeruginosa ,Biology ,GENOMAS ,medicine.disease_cause ,Virology ,Metallo β lactamase ,Microbiology ,food ,Lytic cycle ,Viruses ,Genetics ,medicine ,Pbunalikevirus ,Molecular Biology - Abstract
Pseudomonas aeruginosa is an important cause of infection, especially in immunocompromised patients. In this regard, strains producing carbapenemases, mainly metallo-β-lactamases (MBLs), have become a significant public health concern. Here, we present the complete annotated genome sequence (65.7 kb) of an F8-related lytic myovirus ( Pbunalikevirus genus) that infects MBL-producing P. aeruginosa strains.
- Published
- 2014
42. A Variant Detection Pipeline for Inherited Cardiomyopathy-Associated Genes Using Next-Generation Sequencing
- Author
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Miguel Mitne-Neto, Alexandre C. Pereira, Julia Daher Carneiro Marsiglia, Louise Cerdeira, Edmundo Arteaga-Fernández, José Eduardo Krieger, and Theo G M Oliveira
- Subjects
Genetics ,medicine.diagnostic_test ,Myosin Heavy Chains ,Sequence analysis ,TNNT2 ,Computational Biology ,High-Throughput Nucleotide Sequencing ,Sequence Analysis, DNA ,Biology ,Molecular diagnostics ,DNA sequencing ,Pathology and Forensic Medicine ,Troponin T ,Mutation ,medicine ,Molecular Medicine ,Humans ,MYH7 ,Genetic Testing ,International HapMap Project ,Indel ,Cardiomyopathies ,Cardiac Myosins ,Biomarkers ,Genetic testing - Abstract
In inherited cardiomyopathies, genetic testing is recognized as an enriching procedure in the diagnostic closure of a cardiac condition. Many genetic mutations have been described as pathogenically related to cardiomyopathies, turning next-generation sequencing into an extremely reliable scenario. Here we describe the validation process of a pipeline constructed with a target panel of 74 cardiomyopathy-related genes sequenced using a next-generation sequencing system. Fifty-two samples from a hypertrophic cardiomyopathy casuistic with previous molecular diagnostics (Sanger-sequenced for MYH7, MYBCP3, and TNNT2; 19 positives and 33 negatives) were processed in parallel with a HapMap reference sample (NA12878) applied for a complete panel assessment. Sequencing coverage values were satisfactory, with a mean of 250× (95% CI, 226.03–273.91) and 95.2% of target bases with a coverage of ≥10×. With a total of 567 variants, variant call sensitivity was tested in five scenarios of coverage and variant allele frequency cutoffs. Maximum achieved sensitivity was 96.7% for single-nucleotide variants and 28.5% for indels, and positive predictive values remained above 0.959 during the whole process. Inter- and intra-assay reproducibility values were 89.5% and 87.3%, respectively. After a careful assessment of analytical performance, we infer that the assay presents potential feasibility for application in diagnostic routines, with minimal time requirements and a simple bioinformatics structure.
- Published
- 2014
43. Additional Information Offered By Snpa in Myelodysplastic Syndromes with Excess Blasts (MDS-EB) and Future Perspectives
- Author
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Maria de Lourdes Lopes Ferrari Chauffaille, Miguel Mitne-Neto, and Thiago Rodrigo De Noronha
- Subjects
Candidate gene ,Immunology ,Single-nucleotide polymorphism ,Chromosomal translocation ,Karyotype ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,Molecular biology ,Uniparental disomy ,Loss of heterozygosity ,genomic DNA ,medicine ,Chromosome abnormality - Abstract
Introduction: The detection of chromosomal abnormalities in myelodysplastic syndromes (MDS) supports the diagnosis, classification, prognostic stratification, therapy option, treatment monitoring and better understanding of the biology of disease. The main chromosomal abnormalities of MDS are losses and gains of genetic material, and these changes are among the most important prognostic parameters in IPSS-R. As a consequence, major advances have been achieved in the treatment and survival of patients. However, nearly half of the patients present a normal karyotype, which prevents their further characterization. Therefore, there is the desire to increase the abnormalities detection rate by other methods. Single nucleotide polymorphisms array (SNPa), also referred to as chromosomal microarray, is a sensitive technology used to perform high-resolution genome-wide DNA losses, gains and copy-neutral loss of heterozygosity (CN-LOH). The genomic DNA is hybridized to polymorphic probes which are SNP markers and non-polymorphic probes which are copy number markers, providing information about CN-LOH and copy number alteration (CNA), respectively. Previous studies have shown that the addition of the SNPa to karyotype (KT) increases by 28% the detection rate of cytogenetic abnormalities. Objective: To substantiate this idea we describe two cases of MDS to whom SNPa added valued information to karyotype. Methods: DNA was extracted from bone marrow cells for genomic clonal evaluation. The DNA was digested, amplified, fragmented, labeled and hybridized to the chip (Affymetrix - CytoScan HD®) containing the probes. The chip was scanned to detect the signals' intensity emitted by the hybridized probes which were further analyzed by a software (ChAS) that allows visualization of CNA and CN-LOH. CNA´s analysis relies on the comparison of the obtained signals to a reference diploid DNA signal, and the difference encountered is characterized as loss or gain. CN-LOH analysis is based on two possible nucleotide signals (A or B), which are evaluated to discriminate three genotypes: AA, AB and BB. CN-LOH occurs when one allele is lost and duplicate another, resulting in genotypes AA or BB. Results: Case 1, 64y-male-patient, classified as MDS-EB (WHO 2016), Bone marrow histology showed grade II fibrosis. KT: 46,XY,del(5)(q15q33),del(17)(p11.2)[16] / 46,XY[4]. SNPa: 3p21.31p21.2 CN-LOH; 5q21.1q35.3 loss (CN:1.00); -7; +8; 12p13.33p12.3, 12p12.1p11.22, 12q22q23.3 loss (CN:1.00); -16; 17p13.3p11.2 mosaic loss (CN: 1.50) and -Y. Case 2, 74y-male-patient, classified as MDS-EB (WHO 2016), Bone marrow histology showed grade II/lll fibrosis. KT: 46,XY[15]. SNPa: 21q21.1q22.3 CN-LOH. Discussion and Conclusion: The SNPa has the advantage of detecting genomic alterations regardless of the cell cycle, even when the cell is quiescent or growth is defective. It also enables the identification of CN-LOH (also known as uniparental disomy, UPD), submicroscopic amplifications and deletions that are not detected by KT. On the other hand, SNPa does not allow the identification of balanced translocations and polyploidy. In case 1, after SNPa analysis, some chromosomal abnormalities (−7, +8, −16 and −Y) were found in sporadic metaphases during the KT reanalysis, but had not initially been described because they did not meet the criterion to be considered as a cytogenetic clone. The risk-stratification (IPSS-R) for this patient was intermediate, but the addition of the SNPa results the risk-stratification could be changed to very poor. Seven months after diagnosis the patient developed acute myeloid leukemia and died. In case 2, CN-LOH detected by SNPa could be responsible for homozygosity of mutations in critical genes located in the 21p region, such as RUNX1 that encodes a protein, which is a transcription factor critical in hematopoiesis. Indeed, sequencing of candidate genes in CN-LOH regions should be considered a priority in the search of driver mutations of MDS. Twenty-four months after diagnosis the patient died due to other non-hematologic causes. In Summary, SNPa analysis may add value to KT non-informative results and occasionally reveal cryptic abnormalities not recognized by karyotyping. However, SNPa analysis should be viewed as a complimentary tool. Acknowledgment: The SNPa test was supported by Grupo Fleury Disclosures No relevant conflicts of interest to declare.
- Published
- 2016
44. Terapia Gênica
- Author
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Miguel Mitne Neto and Mayana Zatz
- Subjects
Neurology ,Neurology (clinical) - Published
- 1999
45. Molecular genetic tests for JAK2V617F, Exon12_JAK2 and MPLW515K/L are highly informative in the evaluation of patients suspected to have BCR-ABL1-negative myeloproliferative neoplasms
- Author
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Edgar Gil Rizzatti, Maria de Lourdes Lopes Ferrari Chauffaille, Marcos Tadeu dos Santos, Kozue Miyashiro, and Miguel Mitne-Neto
- Subjects
Polycythaemia ,medicine.medical_specialty ,Pathology ,DNA Mutational Analysis ,Fusion Proteins, bcr-abl ,Short Report ,Real-Time Polymerase Chain Reaction ,Gastroenterology ,Pathology and Forensic Medicine ,Myeloproliferative Disorders ,Internal medicine ,Molecular genetics ,hemic and lymphatic diseases ,medicine ,Cancer Genetics ,Humans ,Janus kinase 2 ,Haematopathology ,biology ,Base Sequence ,Essential thrombocythemia ,General Medicine ,Gene rearrangement ,Exons ,Janus Kinase 2 ,medicine.disease ,Haematopoiesis ,Mutation (genetic algorithm) ,Mutation ,biology.protein ,Haemato-Oncology ,Receptors, Thrombopoietin - Abstract
Polycythaemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (MF), are the most common myeloproliferative neoplasms (MPN) in patients without the BCR-ABL1 gene rearrangement. They are caused by clonal expansion of haematopoietic stem cells and share, as a diagnostic criterion, the identification of JAK2V617F mutation. Classically, when other clinical criteria are present, a JAK2V617F negative case requires the analysis of Exon12_JAK2 for the diagnosis of PV, and of MPL515K/L mutations for the diagnosis of ET and MF. Here, we evaluated 78 samples from Brazilian patients suspected to have MPN, without stratification for PV, ET or MF. We found that 28 (35.9%) are JAK2V617F carriers; from the 50 remaining samples, one (2%) showed an Exon12_JAK2 mutation, and another (2%) was positive for MPLW515L mutation. In summary, the investigation of JAK2V617F, Exon12_JAK2 and MPLW515K/L was relevant for the diagnosis of 38.4% of patients suspected to have BCR-ABL1-negative MPN, suggesting that molecular genetic tests are useful for a quick and unequivocal diagnosis of MPN.
- Published
- 2013
46. In vitro analysis of amyotrophic lateral sclerosis type 8 and genetic study of spastic paraplegia 4
- Author
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Miguel Mitne Neto, Mayana Zatz, Luciana Amaral Haddad, Fernando Kok, Carlos Frederico Martins Menck, and Oswaldo Keith Okamoto
- Abstract
As doenças do neurônio motor (DNM) apresentam grande variabilidade clínica e genética. A Esclerose Lateral Amiotrófica (ELA) é a forma mais comum de DNM de início tardio. Sua manifestação devastadora e incurável leva a uma profunda perda da qualidade de vida do paciente. A ELA8 é uma forma autossômica dominante de ELA familial causada por mutações no gene VAPB. A proteína VAPB está envolvida com diversos processos celulares. Nossos dados sugerem que a mutação P56S na VAPB diminui a interação dela com outras duas outras proteínas: Tubulina e GAPDH. Por terem sido previamente relacionadas a outras formas de doenças neurodegenerativas, essas proteínas são potenciais pontos-chave para desvendar a patogênese da ELA8 e de outras formas de DNM. Um número significativo de drogas testadas com sucesso em modelos animais de ELA não pôde ser transferido para os pacientes, trazendo à tona a necessidade de novos sistemas de estudo da doença. A tecnologia das iPSC torna possível a reprogramação celular para um estágio de pluripotência, permitindo a modelagem de doenças in vitro. Apresentamos um novo modelo de ELA baseado em células iPSC derivadas de pacientes com ELA8. Este modelo apresenta uma redução dos níveis de VAPB quando comparado com os controles. Contudo, não identificamos os agregados intracitoplasmáticos, característicos dos modelos de super-expressão. Mostramos pela primeira vez que células-tronco embrionárias humanas normais expressam VAPB. Adicionalmente, nossos resultados sugerem que os pacientes com ELA8 teriam uma redução dos níveis de VAPB desde o início de suas vidas e revelam a importância de modelar a ELA num background humano. Dessa forma, sugerimos a hipótese de que quantidades específicas de VAPB sejam cruciais para a viabilidade dos neurônios motores. A busca por alterações no número de cópias levou à identificação do primeiro caso de uma duplicação multi-exônica (exon10_12dup) no gene SPG4, ampliando o espectro de mutações encontradas nesse gene. Esta mutação leva à formação de um códon de parada prematuro, sugerindo que a proteína produzida não é funcional. A análise de 30 indivíduos portadores desta mutação mostrou que os homens possuem, na média, idade de início antecipada e quadro clínico mais severo. Esses dados sugerem que certas doenças neuromusculares podem ser moduladas por fatores relacionados ao background individual e ao gênero. Em suma, apoiamos a idéia de que os microtúbulos estariam envolvidos na patogênese das doenças neuromusculares, visto que tanto a VAPB quanto a Espastina interagem com estes elementos do citoesqueleto. Ainda, apresentamos um novo modelo in vitro de análise da ELA e além de justificar os estudos num background humano. The motor neuron diseases (MND) show a huge clinical and genetic variability. Amyotrophic Lateral Sclerosis (ALS) is the most common late-onset form of MND. ALSs devastating and incurable manifestation leads to a profound loss of life quality. ALS8 is an autosomal dominant form of ALS caused by mutations in the VAPB gene. The VAPB protein is involved with many cellular processes and our data suggest that P56S mutation in this protein reduces its interaction with two other proteins: Tubulin and GAPDH. Since these proteins were previously related to other types of neurodegenerative diseases they potentially are key points to reveal the processes responsible for ALS8 and other MND. A substantial number of successful drug tests in ALS animal models could not be translated to humans, showing the need of novel ALS systems. iPSC technology made possible cellular reprogramming. The iPSC technology brings new hope in this area since it can be used to model diseases in vitro. Here we present a new ALS model based on ALS8-iPSC. Compared to control samples, this model shows a reduction of VAPB levels. However, we could not identify intracytoplasmic aggregates, which characterize overexpression models. We show for the first time that human embryonic stem cells express VAPB. Combined with results showing a VAPB reduction in ALS8 samples, it suggests that ALS8 patients present diminished protein levels since the beginning of their lives and reveal the importance of modeling ALS in a human background. The search for copy number variations has led to the identification of the first multiexonic duplication (exon10_12dup) in SPG4 gene, expanding the mutation spectrum in this gene. This mutation leads to a premature stop codon, which suggests that the expressed protein is not functional. The analysis of 30 individuals who carry the mutation showed that males have on average an earlier AAO and are more severely affected. These data suggest specific neuromuscular diseases can be modulated by factors related to individual background and gender. In sum, we support the idea that microtubules can be involved with neuromuscular disorders pathogenesis, since both VAPB and Spastin interact with these cytoskeleton components. Additionally, we present a new in vitro model to ALS analysis and we justify the studies in a human background.
- Published
- 2011
47. A mutation in human VAP-B--MSP domain, present in ALS patients, affects the interaction with other cellular proteins
- Author
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Mayana Zatz, Miguel Mitne-Neto, Carla C. Oliveira, Agnes L. Nishimura, Celso Raul Romero Ramos, Daniel C. Pimenta, Juliana Silva da Luz, and Fernando A. Gonzales
- Subjects
Proline ,Vesicular Transport Proteins ,medicine.disease_cause ,Protein–protein interaction ,Microtubule ,Tubulin ,Protein Interaction Mapping ,medicine ,Escherichia coli ,Serine ,Humans ,Amyotrophic lateral sclerosis ,Cloning, Molecular ,Sequence Deletion ,Genetics ,Mutation ,biology ,Endoplasmic reticulum ,Amyotrophic Lateral Sclerosis ,medicine.disease ,Subcellular localization ,Recombinant Proteins ,Cell biology ,Protein Structure, Tertiary ,Amino Acid Substitution ,biology.protein ,Unfolded protein response ,Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) ,Biotechnology - Abstract
Amyotrophic Lateral Sclerosis (ALS) is the most common adult-onset Motor Neuron Disease (MND), characterized by motor neurons death in the cortex, brainstem and spinal cord. Ten loci linked to Familial ALS have been mapped. ALS8 is caused by a substitution of a proline by a serine in the Vesicle-Associated Membrane Protein-Associated protein-B/C (VAP-B/C). VAP-B belongs to a highly conserved family of proteins implicated in Endoplasmic Reticulum-Golgi and intra-Golgi transport and microtubules stabilization. Previous studies demonstrated that the P56S mutation disrupts the subcellular localization of VAP-B and that this position would be essential for Unfolded Protein Response (UPR) induced by VAP-B. In the present work we expressed and purified recombinant wild-type and P56S mutant VAP-B-MSP domain for the analysis of its interactions with other cellular proteins. Our findings suggest that the P56S mutation may lead to a less stable interaction of this endoplasmic reticulum protein with at least two other proteins: tubulin and GAPDH. These two proteins have been previously related to other forms of neurodegenerative diseases and are potential key points to understand ALS8 pathogenesis and other forms of MND. Understanding the role of these protein interactions may help the treatment of this devastating disease in the future.
- Published
- 2007
48. A multi-exonic SPG4 duplication underlies sex-dependent penetrance of hereditary spastic paraplegia in a large brazilian pedigree
- Author
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Alessandra Starling, Fernando Kok, Mayana Zatz, Guilherme Mitne, Marcilia Martyn, A Cerqueira, M. Valadares, Zodja Graciani, Carlos Bandeira de Mello Monteiro, Miguel Mitne-Neto, Thomas Deufel, André Pessoa, Christian Beetz, Paulo Hubert, Clarissa Bueno, and Anders O H Nygren
- Subjects
Adult ,Male ,Heterozygote ,Spastin ,Adolescent ,Hereditary spastic paraplegia ,Pedigree chart ,Locus (genetics) ,Penetrance ,Kaplan-Meier Estimate ,Biology ,Gene Duplication ,Gene duplication ,Genetics ,medicine ,Humans ,Muscular dystrophy ,Gene ,Genetics (clinical) ,Adenosine Triphosphatases ,Sex Characteristics ,Spastic Paraplegia, Hereditary ,Infant ,Exons ,Middle Aged ,medicine.disease ,GENÉTICA MÉDICA ,Pedigree ,Mutation ,Female ,Brazil - Abstract
SPG4 mutations are the most frequent cause of autosomal-dominant hereditary spastic paraplegia (HSP). SPG4 HSP is characterized by large inter- and intrafamilial variability in age at onset (AAO) and disease severity. The broad spectrum of SPG4 mutations has recently been further extended by the finding of large genomic deletions in SPG4-linked pedigrees negative for 'small' mutations. We had previously reported a very large pedigree, linked to the SPG4 locus with many affected members, which showed gender difference in clinical manifestation. Screening for copy number aberrations revealed the first case of a multi-exonic duplication (exon10_12dup) in the SPG4 gene. The mutation leads to a premature stop codon, suggesting that the protein product is not functional. The analysis of 30 individuals who carry the mutation showed that males have on average an earlier AAO and are more severely affected. The present family suggests that this HSP pathogenesis may be modulated by factors related to individual background and gender as observed for other autosomal dominant conditions, such as facio-scapulohumeral muscular dystrophy or amyloidosis. Understanding why some individuals, particularly women, are 'partially protected' from the effects of this and other pathogenic mutations is of utmost importance.
- Published
- 2007
49. A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis
- Author
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Agnes L. Nishimura, Antonio Richieri-Costa, Helga Cristina Almeida da Silva, Mayana Zatz, Jeanette Webb, Thomas H. Gillingwater, João Ricardo Mendes de Oliveira, Miguel Mitne-Neto, Duilio Cascio, Susan Middleton, Fernando Kok, Paul Skehel, Universidade de São Paulo (USP), Universidade Federal de São Paulo (UNIFESP), Univ Edinburgh, and Univ Calif Los Angeles
- Subjects
Adult ,Models, Molecular ,Pathology ,medicine.medical_specialty ,Green Fluorescent Proteins ,Molecular Sequence Data ,Chromosomes, Human, Pair 20 ,Mutation, Missense ,Vesicular Transport Proteins ,Gene Expression ,Biology ,Muscular Atrophy, Spinal ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,medicine ,Humans ,Missense mutation ,Genetics(clinical) ,Amino Acid Sequence ,Amyotrophic lateral sclerosis ,Cells, Cultured ,Genetics (clinical) ,DNA Primers ,030304 developmental biology ,Primary Lateral Sclerosis ,0303 health sciences ,Amyotrophic Lateral Sclerosis ,Calcium-Binding Proteins ,Chromosome Mapping ,Kv Channel-Interacting Proteins ,Articles ,Sequence Analysis, DNA ,Progressive bulbar palsy ,Spinal muscular atrophy ,Middle Aged ,Motor neuron ,VAPB ,medicine.disease ,Founder Effect ,Pedigree ,Protein Structure, Tertiary ,medicine.anatomical_structure ,Membrane protein ,Sequence Alignment ,Brazil ,030217 neurology & neurosurgery - Abstract
Motor neuron diseases (MNDs) are a group of neurodegenerative disorders with involvement of upper and/or lower motor neurons, such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), progressive bulbar palsy, and primary lateral sclerosis. Recently, we have mapped a new locus for an atypical form of ALS/MND ( atypical amyotrophic lateral sclerosis [ALS8]) at 20q13.3 in a large white Brazilian family. Here, we report the finding of a novel missense mutation in the vesicle-associated membrane protein/synaptobrevin-associated membrane protein B (VAPB) gene in patients from this family. Subsequently, the same mutation was identified in patients from six additional kindreds but with different clinical courses, such as ALS8, late-onset SMA, and typical severe ALS with rapid progression. Although it was not possible to link all these families, haplotype analysis suggests a founder effect. Members of the vesicle-associated proteins are intracellular membrane proteins that can associate with microtubules and that have been shown to have a function in membrane transport. These data suggest that clinically variable MNDs may be caused by a dysfunction in intracellular membrane trafficking. Univ São Paulo, Inst Biociencias, Dept Biol, Human Genome Res Ctr, São Paulo, Brazil Universidade Federal de São Paulo, Sch Med, Anesthesiol Pain & Intens Care Dept, São Paulo, Brazil Univ São Paulo, Hosp Rehabil Craniofacial Anomalies, Genet Serv, Bauru, Brazil Univ Edinburgh, Dept Neurosci, Edinburgh, Midlothian, Scotland Univ Calif Los Angeles, Dept Energy, Inst Mol Biol, Inst Genom & Proteom, Los Angeles, CA USA Universidade Federal de São Paulo, Sch Med, Anesthesiol Pain & Intens Care Dept, São Paulo, Brazil Web of Science
- Published
- 2004
50. A novel locus for late onset amyotrophic lateral sclerosis/motor neurone disease variant at 20q13
- Author
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Miguel Mitne-Neto, Mayana Zatz, Helga Cristina Almeida da Silva, Agnes L. Nishimura, João Ricardo Mendes de Oliveira, and Mariz Vainzof
- Subjects
Adult ,Male ,Pathology ,medicine.medical_specialty ,Neuromuscular disease ,Genetic Linkage ,SOD1 ,Chromosomes, Human, Pair 20 ,Atrophy ,Genetics ,medicine ,Humans ,Amyotrophic lateral sclerosis ,Age of Onset ,Genetics (clinical) ,Primary Lateral Sclerosis ,business.industry ,Amyotrophic Lateral Sclerosis ,Chromosome Mapping ,Progressive bulbar palsy ,Progressive muscular atrophy ,Middle Aged ,medicine.disease ,Pedigree ,Female ,business ,Motor neurone disease ,Letter to JMG - Abstract
Motor neurone disease includes a heterogeneous group of disorders with motor neurone involvement, such as amyotrophic lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, and primary lateral sclerosis. Amyotrophic lateral sclerosis is the most common adult onset form of motor neurone disease and involves the lower and upper motor neurones. It is characterised by progressive muscle weakness and atrophy, with fasciculations associated with hyperreflexia and spasticity. One of the proposed mechanisms for amyotrophic lateral sclerosis is degeneration of the motor neurone because of abnormal levels of toxic products that accumulate in the cell. Death usually occurs by respiratory failure about 2–3 years after the first symptoms.1 About 10% of cases are familial amyotrophic lateral sclerosis, and several loci have been associated with this disease. To date, the only two genes identified have been the zinc–copper superoxide dismutase 1 ( SOD1 ) gene, which is located on chromosome 21 (ALS1, MIM105400), and the Alsin gene, which is located at 2q33 (ALS2, MIM 205100).2–4 Autosomal dominant forms of amyotrophic lateral sclerosis also have been linked to 18q21 (ALS3, MIM 606640), 9q34 (ALS4, MIM 602433), and 15q15.1–q21.1 (ALS5, MIM 602099) and amyotrophic lateral sclerosis–frontotemporal dementia (MIM 105550) to 9q21-22.5–9 Moreover, mutations in Dynein are associated with motor neurone degeneration and defects in retrograde transport. This gene acts in the cellular division, trafficking, and transport of several proteins, such as SOD1 .10,11 More recently, two new loci have been associated with amyotrophic lateral sclerosis. One of them, reported by three independent groups, is on chromosome 16; the other is at 20p.12–14 We report a Caucasian Brazilian family with 26 members distributed in three generations affected by a late onset autosomal dominant motor neurone disease. Clinical and neurological examination of 11 living members was compatible with the diagnosis …
- Published
- 2004
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