123 results on '"Avraham Shaag"'
Search Results
2. Combined loss of LAP1B and LAP1C results in an early onset multisystemic nuclear envelopathy
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Boris Fichtman, Fadia Zagairy, Nitzan Biran, Yiftah Barsheshet, Elena Chervinsky, Ziva Ben Neriah, Avraham Shaag, Michael Assa, Orly Elpeleg, Amnon Harel, and Ronen Spiegel
- Subjects
Science - Abstract
Nuclear envelopathies are a group of diseases caused by genetic mutations in essential nuclear envelope genes. Here, the authors report a nuclear envelopathy with a homozygous nonsense variant in TOR1AIP1 which leads to changes in the nuclear morphology including large nuclear-spanning channels in patients’ fibroblasts.
- Published
- 2019
- Full Text
- View/download PDF
3. Homozygous loss-of-function mutations in MNS1 cause laterality defects and likely male infertility.
- Author
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Asaf Ta-Shma, Rim Hjeij, Zeev Perles, Gerard W Dougherty, Ibrahim Abu Zahira, Stef J F Letteboer, Dinu Antony, Alaa Darwish, Dorus A Mans, Sabrina Spittler, Christine Edelbusch, Sandra Cindrić, Tabea Nöthe-Menchen, Heike Olbrich, Friederike Stuhlmann, Isabella Aprea, Petra Pennekamp, Niki T Loges, Oded Breuer, Avraham Shaag, Azaria J J T Rein, Elif Yilmaz Gulec, Alper Gezdirici, Revital Abitbul, Nael Elias, Israel Amirav, Miriam Schmidts, Ronald Roepman, Orly Elpeleg, and Heymut Omran
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Genetics ,QH426-470 - Abstract
The clinical spectrum of ciliopathies affecting motile cilia spans impaired mucociliary clearance in the respiratory system, laterality defects including heart malformations, infertility and hydrocephalus. Using linkage analysis and whole exome sequencing, we identified two recessive loss-of-function MNS1 mutations in five individuals from four consanguineous families: 1) a homozygous nonsense mutation p.Arg242* in four males with laterality defects and infertility and 2) a homozygous nonsense mutation p.Gln203* in one female with laterality defects and recurrent respiratory infections additionally carrying homozygous mutations in DNAH5. Consistent with the laterality defects observed in these individuals, we found Mns1 to be expressed in mouse embryonic ventral node. Immunofluorescence analysis further revealed that MNS1 localizes to the axonemes of respiratory cilia as well as sperm flagella in human. In-depth ultrastructural analyses confirmed a subtle outer dynein arm (ODA) defect in the axonemes of respiratory epithelial cells resembling findings reported in Mns1-deficient mice. Ultrastructural analyses in the female carrying combined mutations in MNS1 and DNAH5 indicated a role for MNS1 in the process of ODA docking (ODA-DC) in the distal respiratory axonemes. Furthermore, co-immunoprecipitation and yeast two hybrid analyses demonstrated that MNS1 dimerizes and interacts with the ODA docking complex component CCDC114. Overall, we demonstrate that MNS1 deficiency in humans causes laterality defects (situs inversus) and likely male infertility and that MNS1 plays a role in the ODA-DC assembly.
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- 2018
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4. Extending the clinical and immunological phenotype of human interleukin-21 receptor deficiency
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Polina Stepensky, Baerbel Keller, Omar Abuzaitoun, Avraham Shaag, Barak Yaacov, Susanne Unger, Maximilian Seidl, Marta Rizzi, Michael Weintraub, Orly Elpeleg, and Klaus Warnatz
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2015
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5. A deleterious mutation in DNAJC6 encoding the neuronal-specific clathrin-uncoating co-chaperone auxilin, is associated with juvenile parkinsonism.
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Simon Edvardson, Yuval Cinnamon, Asaf Ta-Shma, Avraham Shaag, Yang-In Yim, Shamir Zenvirt, Chaim Jalas, Suzanne Lesage, Alexis Brice, Albert Taraboulos, Klaus H Kaestner, Lois E Greene, and Orly Elpeleg
- Subjects
Medicine ,Science - Abstract
Parkinson disease is caused by neuronal loss in the substantia nigra which manifests by abnormality of movement, muscle tone, and postural stability. Several genes have been implicated in the pathogenesis of Parkinson disease, but the underlying molecular basis is still unknown for ∼70% of the patients. Using homozygosity mapping and whole exome sequencing we identified a deleterious mutation in DNAJC6 in two patients with juvenile parkinsonism. The mutation was associated with abnormal transcripts and marked reduced DNAJC6 mRNA level. DNAJC6 encodes the HSP40 Auxilin, a protein which is selectively expressed in neurons and confers specificity to the ATPase activity of its partner Hcs70 in clathrin uncoating. In Auxilin null mice it was previously shown that the abnormally increased retention of assembled clathrin on vesicles and in empty cages leads to impaired synaptic vesicle recycling and perturbed clathrin mediated endocytosis. Endocytosis function, studied by transferring uptake, was normal in fibroblasts from our patients, likely because of the presence of another J-domain containing partner which co-chaperones Hsc70-mediated uncoating activity in non-neuronal cells. The present report underscores the importance of the endocytic/lysosomal pathway in the pathogenesis of Parkinson disease and other forms of parkinsonism.
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- 2012
- Full Text
- View/download PDF
6. IL-2-inducible T-cell kinase deficiency: clinical presentation and therapeutic approach
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Polina Stepensky, Michael Weintraub, Asaf Yanir, Shoshana Revel-Vilk, Frank Krux, Kirsten Huck, Rene M. Linka, Avraham Shaag, Orly Elpeleg, Arndt Borkhardt, and Igor B. Resnick
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Mutations in the IL-2-inducible T-cell kinase gene have recently been shown to cause an autosomal recessive fatal Epstein Barr virus (EBV) associated lymphoproliferation. We report 3 cases from a single family who presented with EBV-positive B-cell proliferation diagnosed as Hodgkin’s lymphoma. Single nucleotide polymorphism array-based genome-wide linkage analysis revealed IL-2-inducible T-cell kinase as a candidate gene for this disorder. All 3 patients harbored the same novel homozygous nonsense mutation C1764G which causes a premature stop-codon in the kinase domain. All cases were initially treated with chemotherapy. One patient remains in durable remission, the second patient subsequently developed severe hemophagocytic lymphohistiocytosis with multi-organ failure and died, and the third patient underwent a successful allogeneic bone marrow transplantation. IL-2-inducible T-cell kinase deficiency underlies a new primary immune deficiency which may account for part of the spectrum of Epstein Barr virus related lymphoproliferative disorders which can be successfully corrected by bone marrow transplantation.
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- 2011
- Full Text
- View/download PDF
7. A novel de novo heterozygous pathogenic variant in the SDHA gene results in childhood onset bilateral optic atrophy and cognitive impairment
- Author
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Orly Elpeleg, Moshe Dessau, Avraham Shaag, Ronen Spiegel, Yoav Zehavi, Haneen Jabaly-Habib, and Ann Saada
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0301 basic medicine ,Genetics ,SDHB ,Mitochondrial disease ,Respiratory chain complex ,SDHA ,Biology ,medicine.disease ,Biochemistry ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,030104 developmental biology ,0302 clinical medicine ,Atrophy ,medicine ,Neurology (clinical) ,SDHD ,Global developmental delay ,030217 neurology & neurosurgery ,Exome sequencing - Abstract
Isolated defects in the mitochondrial respiratory chain complex II (CII; succinate-ubiquinone oxidoreductase) are extremely rare and mainly result from bi-allelic mutations in one of the nuclear encoded subunits: SDHA, SDHB and SDHD, which comprise CII and the assembly CII factor SDHAF1. We report an adolescent female who presented with global developmental delay, intellectual disability and childhood onset progressive bilateral optic atrophy. Whole exome sequencing of the patient and her unaffected parents identified the novel heterozygous de novo variant c.1984C > T [NM_004168.4] in the SDHA gene. Biochemical assessment of CII in the patient’s derived fibroblasts and lymphocytes displayed considerably decreased CII residual activity compared with normal controls, when normalized to the integral mitochondrial enzyme citrate synthase. Protein modeling of the consequent p.Arg662Cys variant [NP-004159.2] suggested that this substitution will compromise the structural integrity of the FAD-binding protein at the C-terminus that will ultimately impair the FAD binding to SDHA, thus decreasing the entire CII activity. Our study emphasizes the role of certain heterozygous SDHA mutations in a distinct clinical phenotype dominated by optic atrophy and neurological impairment. This is the second mutation that has been reported to cause this phenotype. Furthermore, it adds developmental delay and cognitive disability to the expanding spectrum of the disorder. We propose to add SDHA to next generation sequencing gene panels of optic atrophy.
- Published
- 2021
8. The role of orotic acid measurement in routine newborn screening for urea cycle disorders
- Author
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Naama Yosha-Orpaz, Hatem Khammash, Shlomo Almashanu, Hanna Mandel, Ronella Marom, Ben Pode-Shakked, Avraham Shaag, Taly Vaisid, Avi Zeharia, Dror Mandel, Ayala Blau, Ronen Spiegel, Ann Saada, Eli Hershkovitz, Erez Nadir, Iris Morag, Talya Saraf-Levy, Suha Daas, Nava Shaul Lotan, Rimona Keidar, Yair Anikster, Reeval Segel, Elena Dumin, Galit Tal, Sagi Ben Yehoshua Josefsberg, Elon Pras, Nira Rostami, Tally Lerman-Sagie, Nasser Abu Salah, Tzipora C. Falik-Zaccai, Haike Reznik-Wolf, Ehud Banne, Orna Staretz-Chacham, Yuval Landau, Aviva Fattal-Valevski, Stanley H Korman, Igor Ulanovsky, and Dalit E. Dar
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Male ,medicine.medical_specialty ,Orotic acid ,Gastroenterology ,03 medical and health sciences ,chemistry.chemical_compound ,Neonatal Screening ,Internal medicine ,Genetics ,Citrulline ,Humans ,Medicine ,Israel ,Dried blood ,Urea Cycle Disorders, Inborn ,Genetics (clinical) ,Ornithine transcarbamylase deficiency ,Retrospective Studies ,030304 developmental biology ,Orotic Acid ,0303 health sciences ,Newborn screening ,business.industry ,030305 genetics & heredity ,High mortality ,Infant, Newborn ,food and beverages ,medicine.disease ,Ornithine Carbamoyltransferase Deficiency Disease ,Glutamine ,chemistry ,Urea cycle ,Female ,Dried Blood Spot Testing ,business ,medicine.drug - Abstract
Urea cycle disorders (UCDs), including OTC deficiency (OTCD), are life-threatening diseases with a broad clinical spectrum. Early diagnosis and initiation of treatment based on a newborn screening (NBS) test for OTCD with high specificity and sensitivity may contribute to reduction of the significant complications and high mortality. The efficacy of incorporating orotic acid determination into routine NBS was evaluated. Combined measurement of orotic acid and citrulline in archived dried blood spots from newborns with urea cycle disorders and normal controls was used to develop an algorithm for routine NBS for OTCD in Israel. Clinical information and genetic confirmation results were obtained from the follow-up care providers. About 1147986 newborns underwent routine NBS including orotic acid determination, 25 of whom were ultimately diagnosed with a UCD. Of 11 newborns with OTCD, orotate was elevated in seven but normal in two males with early-onset and two males with late-onset disease. Orotate was also elevated in archived dried blood spots of all seven retrospectively tested historical OTCD patients, only three of whom had originally been identified by NBS with low citrulline and elevated glutamine. Among the other UCDs emerge, three CPS1D cases and additional three retrospective CPS1D cases otherwise reported as a very rare condition. Combined levels of orotic acid and citrulline in routine NBS can enhance the detection of UCD, especially increasing the screening sensitivity for OTCD and differentiate it from CPS1D. Our data and the negligible extra cost for orotic acid determination might contribute to the discussion on screening for proximal UCDs in routine NBS.
- Published
- 2020
9. The many etiologies of nonimmune hydrops fetalis diagnosed by exome sequencing
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Avraham Shaag, Simcha Yagel, Shay Porat, Hagar Mor-Shaked, Duha Fahham, N. Yanai, Hagit Daum, Tova Wagner, Ayala Frumkin, and Vardiella Meiner
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Pediatrics ,medicine.medical_specialty ,Pregnancy ,business.industry ,Hydrops Fetalis ,Pregnancy Outcome ,Obstetrics and Gynecology ,Consanguinity ,medicine.disease ,Lymphedema ,Fetus ,Hydrops fetalis ,Exome Sequencing ,medicine ,Etiology ,Humans ,Exome ,Female ,business ,Pathological ,Genetics (clinical) ,Exome sequencing - Abstract
Objective To explain the importance of identifying an etiology for the pathological finding of nonimmune hydrops fetalis (NIHF) and to explore the impact of exome sequencing in recurrent NIHF. In addition, we present two cases of pregnancies affected with recurrent NIHF, in which genetic investigation was advantageous. Methods Our study aimed to investigate the genetic background, if available, of all fetuses with NIHF referred to our tertiary medical center from January 2013 to August 2020. We summarized the etiology of NIHF if known, sonographic findings, genetic investigation and the pregnancies' outcomes. Results We encountered 144 families with NIHF. Genetic investigation was performed by CMA in 63 (63/144. 44%) fetuses. Seventeen of 63 (27%) had a positive CMA result. In the negative CMA group, 15 (15/46, 33%) opted for exome sequencing, of which seven exomes were positive (47%). Among these, there were four couples with recurrent pregnancies affected by hydrops. Among the remaining 11 exome investigations for non-recurrent hydrops, another three were diagnostic. Conclusion As identifying the etiology of the NIHF is an invaluable tool for the prognosis of the pregnancy, exome sequencing can provide further elucidation of the underlying pathogenesis of NIHF. Thus, genetic investigation should be recommended for cases of NIHF. This article is protected by copyright. All rights reserved.
- Published
- 2021
10. Combined loss of LAP1B and LAP1C results in an early onset multisystemic nuclear envelopathy
- Author
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Michael Assa, Fadia Zagairy, Ronen Spiegel, Orly Elpeleg, Ziva Ben Neriah, Nitzan Biran, Amnon Harel, Boris Fichtman, Avraham Shaag, Elena Chervinsky, and Yiftah Barsheshet
- Subjects
0301 basic medicine ,Gene isoform ,Male ,Nuclear Envelope ,Science ,Nonsense mutation ,DNA Mutational Analysis ,General Physics and Astronomy ,02 engineering and technology ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Fatal Outcome ,Microscopy, Electron, Transmission ,medicine ,Humans ,Protein Isoforms ,Abnormalities, Multiple ,Genetic Predisposition to Disease ,Muscular dystrophy ,Child ,lcsh:Science ,Gene ,Dystonia ,Multidisciplinary ,Base Sequence ,Membrane Proteins ,Nuclear Proteins ,General Chemistry ,021001 nanoscience & nanotechnology ,medicine.disease ,Phenotype ,Cell biology ,Cytoskeletal Proteins ,030104 developmental biology ,Cytoplasm ,Child, Preschool ,Mutation ,Cerebellar atrophy ,Female ,lcsh:Q ,0210 nano-technology - Abstract
Nuclear envelopathies comprise a heterogeneous group of diseases caused by mutations in genes encoding nuclear envelope proteins. Mutations affecting lamina-associated polypeptide 1 (LAP1) result in two discrete phenotypes of muscular dystrophy and progressive dystonia with cerebellar atrophy. We report 7 patients presenting at birth with severe progressive neurological impairment, bilateral cataract, growth retardation and early lethality. All the patients are homozygous for a nonsense mutation in the TOR1AIP1 gene resulting in the loss of both protein isoforms LAP1B and LAP1C. Patient-derived fibroblasts exhibit changes in nuclear envelope morphology and large nuclear-spanning channels containing trapped cytoplasmic organelles. Decreased and inefficient cellular motility is also observed in these fibroblasts. Our study describes the complete absence of both major human LAP1 isoforms, underscoring their crucial role in early development and organogenesis. LAP1-associated defects may thus comprise a broad clinical spectrum depending on the availability of both isoforms in the nuclear envelope throughout life., Nuclear envelopathies are a group of diseases caused by genetic mutations in essential nuclear envelope genes. Here, the authors report a nuclear envelopathy with a homozygous nonsense variant in TOR1AIP1 which leads to changes in the nuclear morphology including large nuclear-spanning channels in patients’ fibroblasts.
- Published
- 2019
11. Heterozygous RNF13 Gain-of-Function Variants Are Associated with Congenital Microcephaly, Epileptic Encephalopathy, Blindness, and Failure to Thrive
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Orly Elpeleg, Claudia M. Nicolae, Anna De Grassi, Jessica Bischetsrieder, Simon Edvardson, Giuseppe Punzi, Jennifer Burton, George Lucian Moldovan, Ciro Leonardo Pierri, Grace J. Noh, and Avraham Shaag
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Male ,Models, Molecular ,0301 basic medicine ,Heterozygote ,Microcephaly ,Developmental Disabilities ,Ubiquitin-Protein Ligases ,Cell ,Apoptosis ,Biology ,Blindness ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,Report ,Genetics ,medicine ,Humans ,Amino Acid Sequence ,Child ,Genetics (clinical) ,Endoplasmic reticulum ,Neurodegeneration ,Infant ,Endoplasmic Reticulum Stress ,medicine.disease ,Failure to Thrive ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Child, Preschool ,Gain of Function Mutation ,Failure to thrive ,Unfolded Protein Response ,Unfolded protein response ,medicine.symptom ,Spasms, Infantile ,030217 neurology & neurosurgery - Abstract
Accumulation of unfolded proteins in the endoplasmic reticulum (ER) initiates a stress response mechanism to clear out the unfolded proteins by either facilitating their re-folding or inducing their degradation. When this fails, an apoptotic cascade is initiated so that the affected cell is eliminated. IRE1α is a critical sensor of the unfolded-protein response, essential for initiating the apoptotic signaling. Here, we report an infantile neurodegenerative disorder associated with enhanced activation of IRE1α and increased apoptosis. Three unrelated affected individuals with congenital microcephaly, infantile epileptic encephalopathy, and profound developmental delay were found to carry heterozygous variants (c.932T>C [p.Leu311Ser] or c.935T>C [p.Leu312Pro]) in RNF13, which codes for an IRE1α-interacting protein. Structural modeling predicted that the variants, located on the surface of the protein, would not alter overall protein folding. Accordingly, the abundance of RNF13 and IRE1α was not altered in affected individuals’ cells. However, both IRE1α-mediated stress signaling and stress-induced apoptosis were increased in affected individuals’ cells. These results indicate that the RNF13 variants confer gain of function to the encoded protein and thereby lead to altered signaling of the ER stress response associated with severe neurodegeneration in infancy.
- Published
- 2019
12. Full genome viral sequences inform patterns of SARS-CoV-2 spread into and within Israel
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Noam Harel, Avi Peretz, Nadav Sorek, Danielle Miller, Naama M. Kopelman, Sharon Amit, Yonat Shemer-Avni, Omer Tirosh, Amit Huppert, Diana Roif-Kaminsky, Katia Koelle, Shiraz Gefen-Halevi, Moran Meir, Avraham Shaag, Adi Stern, Olesya Vorontsov, Dana G. Wolf, Michael A. Martin, and Talia Kustin
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Male ,0301 basic medicine ,Epidemiology ,viruses ,Basic Reproduction Number ,General Physics and Astronomy ,Genome ,law.invention ,0302 clinical medicine ,Communicable Diseases, Imported ,law ,Pandemic ,Israel ,Child ,lcsh:Science ,Phylogeny ,Aged, 80 and over ,Multidisciplinary ,Phylogenetic tree ,Viral Epidemiology ,Middle Aged ,Phylogenetics ,Transmission (mechanics) ,Psychological Distance ,Child, Preschool ,RNA, Viral ,Female ,Viral spread ,Coronavirus Infections ,Adult ,Adolescent ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Secondary infection ,Science ,Pneumonia, Viral ,Genome, Viral ,Biology ,Article ,Virus ,General Biochemistry, Genetics and Molecular Biology ,Betacoronavirus ,Young Adult ,03 medical and health sciences ,Humans ,Pandemics ,Aged ,Base Sequence ,SARS-CoV-2 ,Sequence Analysis, RNA ,Infant, Newborn ,COVID-19 ,Infant ,General Chemistry ,biology.organism_classification ,Virology ,United States ,030104 developmental biology ,Evolutionary biology ,lcsh:Q ,Basic reproduction number ,030217 neurology & neurosurgery - Abstract
Full genome sequences are increasingly used to track the geographic spread and transmission dynamics of viral pathogens. Here, with a focus on Israel, we sequence 212 SARS-CoV-2 sequences and use them to perform a comprehensive analysis to trace the origins and spread of the virus. We find that travelers returning from the United States of America significantly contributed to viral spread in Israel, more than their proportion in incoming infected travelers. Using phylodynamic analysis, we estimate that the basic reproduction number of the virus was initially around 2.5, dropping by more than two-thirds following the implementation of social distancing measures. We further report high levels of transmission heterogeneity in SARS-CoV-2 spread, with between 2-10% of infected individuals resulting in 80% of secondary infections. Overall, our findings demonstrate the effectiveness of social distancing measures for reducing viral spread., In this study, Adi Stern and colleagues use full genome sequences of SARS-CoV-2 to look at the rate of infections in Israel. They report that social distancing had a significant effect on minimising the rate of transmission, and find evidence for transmission heterogeneity (superspreading events).
- Published
- 2020
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- View/download PDF
13. A mutation in POLR3E impairs antiviral immune response and RNA polymerase III
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Iris Fried, Orly Elpeleg, Natalie Orlovetskie, Moshe Kotler, Orly Marcu, Avraham Shaag, Raphael Serruya, Dana G. Wolf, Dhivakar Mani, Aravind Ramanathan, Esther Djian, Polina Stepensky, Alexander Rouvinski, Yiska Weisblum, Nayef Jarrous, Michael Weintraub, and Shoshana Revel-Vilk
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Human cytomegalovirus ,viruses ,Cytomegalovirus ,RNA polymerase III ,Gene Expression Regulation, Enzymologic ,chemistry.chemical_compound ,Transcription (biology) ,RNA polymerase ,Chlorocebus aethiops ,medicine ,Animals ,Humans ,Gene ,Vero Cells ,Polymerase ,Multidisciplinary ,biology ,RNA Polymerase III ,DNA virus ,RNA virus ,Dendritic Cells ,Fibroblasts ,Biological Sciences ,medicine.disease ,biology.organism_classification ,Virology ,chemistry ,Mutation ,biology.protein - Abstract
RNA polymerase (Pol) III has a noncanonical role of viral DNA sensing in the innate immune system. This polymerase transcribes viral genomes to produce RNAs that lead to induction of type I interferons (IFNs). However, the genetic and functional links of Pol III to innate immunity in humans remain largely unknown. Here, we describe a rare homozygous mutation (D40H) in the POLR3E gene, coding for a protein subunit of Pol III, in a child with recurrent and systemic viral infections and Langerhans cell histiocytosis. Fibroblasts derived from the patient exhibit impaired induction of type I IFN and increased susceptibility to human cytomegalovirus (HCMV) infection. Cultured cell lines infected with HCMV show induction of POLR3E expression. However, induction is not restricted to DNA virus, as sindbis virus, an RNA virus, enhances the expression of this protein. Likewise, foreign nonviral DNA elevates the steady-state level of POLR3E and elicits promoter-dependent and -independent transcription by Pol III. Remarkably, the molecular mechanism underlying the D40H mutation of POLR3E involves the assembly of defective initiation complexes of Pol III. Our study links mutated POLR3E and Pol III to an innate immune deficiency state in humans.
- Published
- 2020
14. A novel de novo heterozygous pathogenic variant in the SDHA gene results in childhood onset bilateral optic atrophy and cognitive impairment
- Author
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Yoav, Zehavi, Ann, Saada, Haneen, Jabaly-Habib, Moshe, Dessau, Avraham, Shaag, Orly, Elpeleg, and Ronen, Spiegel
- Subjects
Heterozygote ,Optic Atrophy ,Adolescent ,Electron Transport Complex II ,Genetic Variation ,Humans ,Cognitive Dysfunction ,Female ,Amino Acid Sequence ,Protein Structure, Secondary - Abstract
Isolated defects in the mitochondrial respiratory chain complex II (CII; succinate-ubiquinone oxidoreductase) are extremely rare and mainly result from bi-allelic mutations in one of the nuclear encoded subunits: SDHA, SDHB and SDHD, which comprise CII and the assembly CII factor SDHAF1. We report an adolescent female who presented with global developmental delay, intellectual disability and childhood onset progressive bilateral optic atrophy. Whole exome sequencing of the patient and her unaffected parents identified the novel heterozygous de novo variant c.1984C T [NM_004168.4] in the SDHA gene. Biochemical assessment of CII in the patient's derived fibroblasts and lymphocytes displayed considerably decreased CII residual activity compared with normal controls, when normalized to the integral mitochondrial enzyme citrate synthase. Protein modeling of the consequent p.Arg662Cys variant [NP-004159.2] suggested that this substitution will compromise the structural integrity of the FAD-binding protein at the C-terminus that will ultimately impair the FAD binding to SDHA, thus decreasing the entire CII activity. Our study emphasizes the role of certain heterozygous SDHA mutations in a distinct clinical phenotype dominated by optic atrophy and neurological impairment. This is the second mutation that has been reported to cause this phenotype. Furthermore, it adds developmental delay and cognitive disability to the expanding spectrum of the disorder. We propose to add SDHA to next generation sequencing gene panels of optic atrophy.
- Published
- 2020
15. Mutations in TRAPPC12 Manifest in Progressive Childhood Encephalopathy and Golgi Dysfunction
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Michael Sacher, Avraham Shaag, Michael O. Dorschner, Miroslav P. Milev, David S. Hanna, Christopher J. Hale, Ian A. Glass, Yong-Han Hank Cheng, Dan Doherty, Keshika Prematilake, Simon Edvardson, Megan E. Grout, Djenann Saint-Dic, and Orly Elpeleg
- Subjects
Male ,0301 basic medicine ,Microcephaly ,Encephalopathy ,Golgi Apparatus ,Endoplasmic Reticulum ,03 medical and health sciences ,symbols.namesake ,Report ,Genetics ,medicine ,Humans ,Exome ,Genetic Predisposition to Disease ,Cells, Cultured ,Genetics (clinical) ,Brain Diseases ,Base Sequence ,biology ,Endoplasmic reticulum ,Brain ,Infant ,Membrane Transport Proteins ,Sequence Analysis, DNA ,Golgi apparatus ,medicine.disease ,Magnetic Resonance Imaging ,Phenotype ,Transport protein ,Protein Transport ,030104 developmental biology ,TRAPP complex ,Membrane protein ,Child, Preschool ,biology.protein ,symbols ,Female ,Atrophy ,Transcription Factors - Abstract
Progressive childhood encephalopathy is an etiologically heterogeneous condition characterized by progressive central nervous system dysfunction in association with a broad range of morbidity and mortality. The causes of encephalopathy can be either non-genetic or genetic. Identifying the genetic causes and dissecting the underlying mechanisms are critical to understanding brain development and improving treatments. Here, we report that variants in TRAPPC12 result in progressive childhood encephalopathy. Three individuals from two unrelated families have either a homozygous deleterious variant (c.145delG [p.Glu49Argfs∗14]) or compound-heterozygous variants (c.360dupC [p.Glu121Argfs∗7] and c.1880C>T [p. Ala627Val]). The clinical phenotypes of the three individuals are strikingly similar: severe disability, microcephaly, hearing loss, spasticity, and characteristic brain imaging findings. Fibroblasts derived from all three individuals showed a fragmented Golgi that could be rescued by expression of wild-type TRAPPC12. Protein transport from the endoplasmic reticulum to and through the Golgi was delayed. TRAPPC12 is a member of the TRAPP protein complex, which functions in membrane trafficking. Variants in several other genes encoding members of the TRAPP complex have been associated with overlapping clinical presentations, indicating shared and distinct functions for each complex member. Detailed understanding of the TRAPP-opathies will illuminate the role of membrane protein transport in human disease.
- Published
- 2017
16. Grandparental genotyping enhances exome variant interpretation
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Hagar Mor-Shaked, Orly Elpeleg, Avraham Shaag, Tamar Harel, Asaf Ta-Shma, Vardiella Meiner, Hagit Daum, Mordechai Shohat, and Shira Silverstein
- Subjects
0301 basic medicine ,Proband ,Adult ,Male ,Parents ,Genotype ,030105 genetics & heredity ,Biology ,03 medical and health sciences ,Hypoplastic Left Heart Syndrome ,Exome Sequencing ,Genetics ,Humans ,Exome ,Genetic Predisposition to Disease ,Genetic Testing ,Receptor, Notch1 ,Child ,Genotyping ,Genetics (clinical) ,Exome sequencing ,Epilepsy ,Mosaicism ,SOXE Transcription Factors ,Infant, Newborn ,Data interpretation ,Grandparent ,Penetrance ,Grandparents ,Repressor Proteins ,030104 developmental biology ,Mutation ,Female - Abstract
Trio exome sequencing is a powerful tool in the molecular investigation of monogenic disorders and provides an incremental diagnostic yield over proband-only sequencing, mainly due to the rapid identification of de novo disease-causing variants. However, heterozygous variants inherited from unaffected parents may be inadvertently dismissed, although multiple explanations are available for such scenarios including mosaicism in the parent, incomplete penetrance, imprinting, or skewed X-inactivation. We report three probands, in which a pathogenic or likely pathogenic variant was identified upon exome sequencing, yet was inherited from an unaffected parent. Segregation of the variants (in NOTCH1, PHF6, and SOX10) in the grandparent generation revealed that the variant was de novo in each case. Additionally, one proband had skewed X-inactivation. We discuss the possible genetic mechanism in each case, and urge caution in data interpretation of exome sequencing data. We illustrate the utility of expanding segregation studies to the grandparent generation and demonstrate the impact on exome interpretation strategies, by showing that objective genotype data can overcome subjective parental report of lack of symptoms.
- Published
- 2019
17. Congenital valvular defects associated with deleterious mutations in thePLD1gene
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Asaf Ta-Shma, Aaron M. Neiman, Kai Zhang, Ekaterina Salimova, Orly Elpeleg, Alma Zernecke, Milena B. Furtado, Azaria J.J.T. Rein, Daniel Sieiro-Mosti, Avraham Shaag, Bernhard Nieswandt, Nadia Rosenthal, David Stegner, and Zeev Perles
- Subjects
0301 basic medicine ,Regulation of gene expression ,Mutation ,Pathology ,medicine.medical_specialty ,Right atrial enlargement ,Anatomy ,Biology ,medicine.disease ,medicine.disease_cause ,Phenotype ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Knockout mouse ,Genetics ,Homologous chromosome ,medicine ,Mitral valve prolapse ,Ventricular outflow tract ,medicine.symptom ,030217 neurology & neurosurgery ,Genetics (clinical) - Abstract
BACKGROUND The underlying molecular aetiology of congenital heart defects is largely unknown. The aim of this study was to explore the genetic basis of non-syndromic severe congenital valve malformations in two unrelated families. METHODS Whole-exome analysis was used to identify the mutations in five patients who suffered from severe valvular malformations involving the pulmonic, tricuspid and mitral valves. The significance of the findings was assessed by studying sporulation of yeast carrying a homologous Phospholipase D (PLD1) mutation, in situ hybridisation in chick embryo and echocardiography and histological examination of hearts of PLD1 knockout mice. RESULTS Three mutations, p.His442Pro, p.Thr495fs32* and c.2882+2T>C, were identified in the PLD1 gene. The mutations affected highly conserved sites in the PLD1 protein and the p.His442Pro mutation produced a strong loss of function phenotype in yeast homologous mutant strain. Here we show that in chick embryos PLD1 expression is confined to the forming heart (E2-E8) and homogeneously expressed all over the heart during days E2-E3. Thereafter its expression decreases, remaining only adjacent to the atrioventricular valves and the right ventricular outflow tract. This pattern of expression follows the known dynamic patterning of apoptosis in the developing heart, consistent with the known role of PLD1 in the promotion of apoptosis. In hearts of PLD1 knockout mice, we detected marked tricuspid regurgitation, right atrial enlargement, and increased flow velocity, narrowing and thickened leaflets of the pulmonic valve. CONCLUSIONS The findings support a role for PLD1 in normal heart valvulogenesis.
- Published
- 2016
18. Extending the Clinical Phenotype of Adenosine Deaminase 2 Deficiency
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Michael S. Hershfield, Yackov Berkun, Tal Ben-Ami, Orly Elpeleg, Michael Weintraub, Polina Stepensky, Shoshana Revel-Vilk, Susan J. Kelly, Nancy J. Ganson, Rebecca Brooks, Shlomit Kfir-Erenfeld, and Avraham Shaag
- Subjects
Male ,0301 basic medicine ,Adenosine Deaminase 2 Deficiency ,Adenosine Deaminase ,Pure red cell aplasia ,03 medical and health sciences ,0302 clinical medicine ,Adenosine deaminase ,Humans ,Medicine ,Diamond–Blackfan anemia ,Child ,Clinical phenotype ,Exome sequencing ,030203 arthritis & rheumatology ,biology ,business.industry ,Infant ,medicine.disease ,Phenotype ,030104 developmental biology ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Immunology ,biology.protein ,Intercellular Signaling Peptides and Proteins ,Female ,business ,Vasculitis ,Metabolism, Inborn Errors - Abstract
Adenosine deaminase 2 deficiency is an autoinflammatory disease, characterized by various forms of vasculitis. We describe 5 patients with adenosine deaminase 2 deficiency with various hematologic manifestations, including pure red cell aplasia, with no evidence for vasculitis.
- Published
- 2016
19. Mutations in the phosphatidylinositol glycan C (PIGC) gene are associated with epilepsy and intellectual disability
- Author
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Simon Edvardson, Anik St-Denis, Philippe M. Campeau, Orly Elpeleg, Yenan T. Bryceson, Yoshiko Murakami, Bassam Abu-Libdeh, Thi Tuyet Mai Nguyen, Françoise Le Deist, Avraham Shaag, Maher Shahrour, Nadira Damseh, and Taroh Kinoshita
- Subjects
0301 basic medicine ,Genetics ,CD48 ,030105 genetics & heredity ,Biology ,Disease gene identification ,Compound heterozygosity ,03 medical and health sciences ,030104 developmental biology ,Global developmental delay ,Disease-causing Mutation ,Gene ,Exome ,Genetics (clinical) ,Exome sequencing - Abstract
Background Of our 1400 exome-studied patients, 67% originate from consanguineous families. ∼80% suffer from variable degree of intellectual disability (ID). The search for disease causing genes using homozygosity mapping was progressing slowly until 2010, then markedly accelerated by the introduction of exome analysis. Objectives To identify the disease causing mutation(s) in three patients from two unrelated families who suffered from global developmental delay, severe ID and drug-responsive seizure disorder. Methods Exome analysis was performed in DNA of the three patients. The identified PIGC variants were generated and transfected into PIGC-defective mouse cells and the restoration of the surface expression of mouse CD90, CD48 and FLAER was assessed using flow cytometry. The expression of these proteins was also studied on the surface of patients9 leucocytes. Results Three PIGC mutations were identified; homozygous p.L189W in one family and compound heterozygosity for p.L212P/p.R21X variants in another. PIGC participates in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor which tethers proteins to plasma membrane. In cells lacking PIGC protein, which were transfected with each of the PIGC variants, we detected a clear reduction of surface expression of GPI-anchored proteins. Furthermore, analyses of patients9 leucocytes showed significant and constant decrease of CD16 surface expression in granulocytes, and moderate decrease of CD14, CD55, CD59 and FLAER levels. Conclusions PIGC joins the list of genes in which mutations result in defective biosynthesis of GPI anchoring, manifesting by global developmental delay and seizure disorder. The lack of specific biomarker dictates exome sequencing as the diagnostic procedure of choice in similar patients.
- Published
- 2016
20. Mitochondrial hepato-encephalopathy due to deficiency of QIL1/MIC13 (C19orf70), a MICOS complex subunit
- Author
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Ann Saada, Avraham Zeharia, Osnat Konen, Orly Elpeleg, Jonathan R. Friedman, Ana Tobar, Avraham Shaag, Yacov Fellig, and Jodi Nunnari
- Subjects
Male ,0301 basic medicine ,Mitochondrial Diseases ,Protein subunit ,Mitochondrion ,Biology ,Article ,Mitochondrial Proteins ,Open Reading Frames ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,Humans ,Inner membrane ,Respiratory function ,Inner mitochondrial membrane ,Cells, Cultured ,Genetics (clinical) ,Brain Diseases ,MICOS complex ,Liver Diseases ,DNAJC19 ,Infant ,Syndrome ,Fibroblasts ,Mitochondria ,Cell biology ,030104 developmental biology ,Mitochondrial matrix ,Child, Preschool ,Female ,030217 neurology & neurosurgery - Abstract
The mitochondrial inner membrane possesses distinct subdomains including cristae, which are lamellar structures invaginated into the mitochondrial matrix and contain the respiratory complexes. Generation of inner membrane domains requires the complex interplay between the respiratory complexes, mitochondrial lipids and the recently identified mitochondrial contact site and cristae organizing system (MICOS) complex. Proper organization of the mitochondrial inner membrane has recently been shown to be important for respiratory function in yeast. Here we aimed at a molecular diagnosis in a brother and sister from a consanguineous family who presented with a neurodegenerative disorder accompanied by hyperlactatemia, 3-methylglutaconic aciduria, disturbed hepatocellular function with abnormal cristae morphology in liver and cerebellar and vermis atrophy, which suggest mitochondrial dysfunction. Using homozygosity mapping and exome sequencing the patients were found to be homozygous for the p.(Gly15Glufs*75) variant in the QIL1/MIC13 (C19orf70) gene. QIL1/MIC13 is a constituent of MICOS, a six subunit complex that helps to form and/or stabilize cristae junctions and determine the placement, distribution and number of cristae within mitochondria. In patient fibroblasts both MICOS subunits QIL1/MIC13 and MIC10 were absent whereas MIC60 was present in a comparable abundance to that of the control. We conclude that QIL1/MIC13 deficiency in human, is associated with disassembly of the MICOS complex, with the associated aberration of cristae morphology and mitochondrial respiratory dysfunction. 3-Methylglutaconic aciduria is associated with variants in genes encoding mitochondrial inner membrane organizing determinants, including TAZ, DNAJC19, SERAC1 and QIL1/MIC13.
- Published
- 2016
21. A mutation in the THG1L gene in a family with cerebellar ataxia and developmental delay
- Author
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Ashanti O. Matlock, Jane E. Jackman, Avraham Shaag, Katherine Labbé, Krishna J. Patel, Chaim Jalas, Yael Elbaz-Alon, Orly Elpeleg, and Simon Edvardson
- Subjects
Male ,0301 basic medicine ,Cerebellar Ataxia ,Developmental Disabilities ,Mitochondrial disease ,Purkinje cell ,MFN2 ,Biology ,Mitochondrion ,Mitochondrial Dynamics ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Genetics ,medicine ,Humans ,Genetics (clinical) ,Cerebellar ataxia ,Siblings ,Homozygote ,Brain ,Proteins ,medicine.disease ,Magnetic Resonance Imaging ,Molecular biology ,Pedigree ,030104 developmental biology ,medicine.anatomical_structure ,mitochondrial fusion ,Guanylyltransferase activity ,Mutation ,Female ,Cerebellar atrophy ,medicine.symptom ,030217 neurology & neurosurgery - Abstract
Autosomal-recessive cerebellar atrophy is usually associated with inactivating mutations and early-onset presentation. The underlying molecular diagnosis suggests the involvement of neuronal survival pathways, but many mechanisms are still lacking and most patients elude genetic diagnosis. Using whole exome sequencing, we identified homozygous p.Val55Ala in the THG1L (tRNA-histidine guanylyltransferase 1 like) gene in three siblings who presented with cerebellar signs, developmental delay, dysarthria, and pyramidal signs and had cerebellar atrophy on brain MRI. THG1L protein was previously reported to participate in mitochondrial fusion via its interaction with MFN2. Abnormal mitochondrial fragmentation, including mitochondria accumulation around the nuclei and confinement of the mitochondrial network to the nuclear vicinity, was observed when patient fibroblasts were cultured in galactose containing medium. Culturing cells in galactose containing media promotes cellular respiration by oxidative phosphorylation and the action of the electron transport chain thus stimulating mitochondrial activity. The growth defect of the yeast thg1Δ strain was rescued by the expression of either yeast Thg1 or human THG1L; however, clear growth defect was observed following the expression of the human p.Val55Ala THG1L or the corresponding yeast mutant. A defect in the protein tRNAHis guanylyltransferase activity was excluded by the normal in vitro G-1 addition to either yeast tRNAHis or human mitochondrial tRNAHis in the presence of the THG1L mutation. We propose that homozygosity for the p.Val55Ala mutation in THG1L is the cause of the abnormal mitochondrial network in the patient fibroblasts, likely by interfering with THG1L activity towards MFN2. This may result in lack of mitochondria in the cerebellar Purkinje dendrites, with degeneration of Purkinje cell bodies and apoptosis of granule cells, as reported for MFN2 deficient mice.
- Published
- 2016
22. The use of whole exome sequencing for the diagnosis of autosomal recessive malignant infantile osteopetrosis
- Author
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Adeeb NaserEddin, Michael Weintraub, Oded Shamriz, Avraham Shaag, Polina Stepensky, Barak Yaacov, and Orly Elpeleg
- Subjects
0301 basic medicine ,Genetics ,biology ,business.industry ,Increased Bone Density ,Osteopetrosis ,medicine.disease ,TCIRG1 ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,biology.protein ,Medicine ,Congenital disease ,CLCN7 ,business ,Mendelian disorders ,Genetics (clinical) ,Exome sequencing - Abstract
Autosomal recessive malignant infantile osteopetrosis is a congenital disease characterized by pathologically increased bone density. Recently, the use of whole exome sequencing has been utilized as a clinical diagnostic tool in a number of Mendelian disorders. In this study, whole exome sequencing (WES) was successfully used in six patients with malignant infantile osteopetrosis (MIOP) and identified mutations in four MIOP-related genes (CLCN7, TCIRG1, SNX10, and TNFRSF11A). We report these patients, describe the mutations and review the current literature.
- Published
- 2016
23. Early onset combined immunodeficiency and autoimmunity in patients with loss-of-function mutation in LAT
- Author
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Irina Zaidman, Jerry Stein, Klaus Warnatz, Amir A. Kuperman, O. Sascha Yousefi, Mikael Sigvardsson, Polina Stepensky, Wolfgang W. A. Schamel, Dov Hershkovitz, Orly Elpeleg, Avraham Shaag, Baerbel Keller, Kristina Schachtrup, and Susanne Unger
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Autoimmune disease ,Kinase ,Cell- och molekylärbiologi ,T cell ,Immunology ,Linker for Activation of T cells ,Biology ,medicine.disease ,medicine.disease_cause ,Autoimmunity ,03 medical and health sciences ,030104 developmental biology ,Immune system ,medicine.anatomical_structure ,medicine ,Cancer research ,Immunology and Allergy ,Cell and Molecular Biology ,Immunodeficiency - Abstract
The adapter protein linker for activation of T cells (LAT) is a critical signaling hub connecting T cell antigen receptor triggering to downstream T cell responses. In this study, we describe the first kindred with defective LAT signaling caused by a homozygous mutation in exon 5, leading to a premature stop codon deleting most of the cytoplasmic tail of LAT, including the critical tyrosine residues for signal propagation. The three patients presented from early childhood with combined immunodeficiency and severe autoimmune disease. Unlike in the mouse counterpart, reduced numbers of T cells were present in the patients. Despite the reported nonredundant role of LAT in Ca2+ mobilization, residual T cells were able to induce Ca2+ influx and nuclear factor (NF) kappa B signaling, whereas extracellular signal-regulated kinase (ERK) signaling was completely abolished. This is the first report of a LAT-related disease in humans, manifesting by a progressive combined immune deficiency with severe autoimmune disease. Funding Agencies|German Federal Ministry of Education and Research [BMBF 01EO1303]; Deutsche Forschungsgemeinschaft [DFG WA 1597/4-1]; Hebrew University; Hadassah Medical Center; Excellence Initiative of the German Research Foundation (Spemann Graduate School) [GSC-4]
- Published
- 2016
24. Homozygous mutation in the APOA1BP is associated with a lethal infantile leukoencephalopathy
- Author
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Avraham Shaag, Ronen Spiegel, Stavit A. Shalev, and Orly Elpeleg
- Subjects
Male ,0301 basic medicine ,Racemases and Epimerases ,Biology ,medicine.disease_cause ,Leukoencephalopathy ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,0302 clinical medicine ,Leukoencephalopathies ,Aspartic acid ,Genetics ,medicine ,Humans ,Gene ,Genetics (clinical) ,Exome sequencing ,Mutation ,Nicotinamide ,Siblings ,Homozygote ,Infant ,Disease gene identification ,medicine.disease ,Molecular biology ,Pedigree ,030104 developmental biology ,chemistry ,Female ,NAD+ kinase ,Carrier Proteins ,030217 neurology & neurosurgery - Abstract
Febrile-induced neurodegenerative diseases are a heterogeneous group of genetic disorders most commonly inborn errors of metabolism that result in irreversible damage involving the central nervous system. Here, we report on five siblings of consanguineous family who developed normally for the first 6–12 months of life then presented with a severe leukoencephalopathy following a trivial febrile illness. Using homozygosity mapping followed by whole exome sequencing, we identified a homozygous c. 281C>A mutation in the APOA1BP gene resulting in substitution of a highly conserved alanine residue with aspartic acid (p.Ala94Asp). APOA1BP encodes for epimerase that catalyzes the R to S epimerization of NAD(P)XH, a crucial step in the dehydration of these toxic metabolites accumulating during cellular metabolism. This is the first report of a defect in the nicotinamide nucleotide repair system in humans.
- Published
- 2016
25. Mutated MCM9 is associated with predisposition to hereditary mixed polyposis and colorectal cancer in addition to primary ovarian failure
- Author
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Yael Goldberg, Morasha Plesser-Duvdevani, Naama Halpern, Vardiella Meiner, Ayala Hubert, Samuel N. Adler, Sherri Cohen, Orit Pappo, and Avraham Shaag
- Subjects
Adult ,Cancer Research ,Colorectal cancer ,Adenomatous polyposis coli ,Primary Ovarian Insufficiency ,Biology ,medicine.disease_cause ,DNA sequencing ,Consanguinity ,Hypergonadotropic hypogonadism ,Chromosomal Instability ,Chromosome instability ,Genetics ,medicine ,Humans ,Molecular Biology ,Exome sequencing ,Mutation ,Minichromosome Maintenance Proteins ,medicine.disease ,Disease gene identification ,Pedigree ,Adenomatous Polyposis Coli ,biology.protein ,Female ,Colorectal Neoplasms - Abstract
Mutations in MCM9, which encodes DNA helicase, were recently shown to cause a clinical phenotype of primary ovarian failure and chromosomal instability. MCM9 plays an essential role in homologous recombination-mediated double-strand break repair. We describe a multiplex family with early colorectal carcinoma and mixed polyposis associated with primary hypergonadotropic hypogonadism. A combination of whole genome homozygosity mapping as well as exome sequencing and targeted gene sequencing identified a homozygous c.672_673delGGinsC mutation that predicts a truncated protein, p.Glu225Lysfs*4. Our data expand the phenotypic spectrum of MCM9 mutations and suggest a link between MCM9 and inherited predisposition to mixed polyposis and early-onset colorectal cancer.
- Published
- 2015
26. Fatal infantile mitochondrial encephalomyopathy, hypertrophic cardiomyopathy and optic atrophy associated with a homozygousOPA1mutation
- Author
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Padraig J. Flannery, Avraham Shaag, Florence Burté, Laurence A. Bindoff, Morad Khayat, Stavit A. Shalev, Verónica Eisner, Robert W. Taylor, Patrick Yu-Wai-Man, Hanna Mandel, Ann Saada, Orly Elpeleg, Eugene Vladovski, Ora Schuler-Furman, Ronen Spiegel, Devorah Soiferman, Yu Wai Man, Patrick [0000-0001-7847-9320], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,Mitochondrial encephalomyopathy ,Mitochondrial DNA ,Metabolic disorders ,Neuroophthalmology ,Biology ,GTP Phosphohydrolases ,03 medical and health sciences ,0302 clinical medicine ,Atrophy ,Mitochondrial Encephalomyopathies ,Pregnancy ,Genetics ,medicine ,Humans ,Clinical genetics ,Muscle, Skeletal ,Genetics (clinical) ,Exome sequencing ,Genotype-Phenotype Correlations ,Homozygote ,Infant ,Mitochondrial membrane fusion ,Neuromuscular disease ,Cardiomyopathy, Hypertrophic ,medicine.disease ,3. Good health ,Optic Atrophy ,030104 developmental biology ,Mitochondrial respiratory chain ,Mitochondrial biogenesis ,Mutation ,Female ,030217 neurology & neurosurgery - Abstract
BACKGROUND: Infantile-onset encephalopathy and hypertrophic cardiomyopathy caused by mitochondrial oxidative phosphorylation defects are genetically heterogeneous with defects involving both the mitochondrial and nuclear genomes. OBJECTIVE: To identify the causative genetic defect in two sisters presenting with lethal infantile encephalopathy, hypertrophic cardiomyopathy and optic atrophy. METHODS: We describe a comprehensive clinical, biochemical and molecular genetic investigation of two affected siblings from a consanguineous family. Molecular genetic analysis was done by a combined approach involving genome-wide autozygosity mapping and next-generation exome sequencing. Biochemical analysis was done by enzymatic analysis and Western blot. Evidence for mitochondrial DNA (mtDNA) instability was investigated using long-range and real-time PCR assays. Mitochondrial cristae morphology was assessed with transmission electron microscopy. RESULTS: Both affected sisters presented with a similar cluster of neurodevelopmental deficits marked by failure to thrive, generalised neuromuscular weakness and optic atrophy. The disease progression was ultimately fatal with severe encephalopathy and hypertrophic cardiomyopathy. Mitochondrial respiratory chain complex activities were globally decreased in skeletal muscle biopsies. They were found to be homozygous for a novel c.1601T>G (p.Leu534Arg) mutation in the OPA1 gene, which resulted in a marked loss of steady-state levels of the native OPA1 protein. We observed severe mtDNA depletion in DNA extracted from the patients' muscle biopsies. Mitochondrial morphology was consistent with abnormal mitochondrial membrane fusion. CONCLUSIONS: We have established, for the first time, a causal link between a pathogenic homozygous OPA1 mutation and human disease. The fatal multisystemic manifestations observed further extend the complex phenotype associated with pathogenic OPA1 mutations, in particular the previously unreported association with hypertrophic cardiomyopathy. Our findings further emphasise the vital role played by OPA1 in mitochondrial biogenesis and mtDNA maintenance.
- Published
- 2015
27. Clues and challenges in the diagnosis of intermittent maple syrup urine disease
- Author
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Avraham Shaag, Suha Daas, Elon Pras, Ben Pode-Shakked, Smadar Abraham, Talya Saraf-Levy, Naomi Pode-Shakked, Shlomo Almashanu, Yuval Landau, Stanley H Korman, Haike Reznik-Wolf, Katya Kneller, Asaf Vivante, Yair Anikster, and Igor Ulanovsky
- Subjects
Male ,0301 basic medicine ,Pediatrics ,medicine.medical_specialty ,Ataxia ,Adolescent ,BCKDHB ,BCKDHA ,030105 genetics & heredity ,Asymptomatic ,03 medical and health sciences ,Maple Syrup Urine Disease ,Valine ,Genetics ,Humans ,Medicine ,Genetic Testing ,Child ,Genetics (clinical) ,Newborn screening ,business.industry ,Maple syrup urine disease ,General Medicine ,medicine.disease ,Phenotype ,030104 developmental biology ,Child, Preschool ,Mutation ,Disease Progression ,Female ,Leucine ,medicine.symptom ,business ,Protein Kinases - Abstract
Background Maple syrup urine disease is a rare autosomal-recessive aminoacidopathy, caused by deficient branched-chain 2-keto acid dehydrogenase (BCKD), with subsequent accumulation of branched-chain amino acids (BCAAs): leucine, isoleucine and valine. While most cases of MSUD are classic, some 20% of cases are non-classic variants, designated as intermediate- or intermittent-types. Patients with the latter form usually develop normally and are cognitively intact, with normal BCAA levels when asymptomatic. However, intercurrent febrile illness and catabolism may cause metabolic derailment with life-threatening neurological sequelae. Thus, early detection and dietary intervention are warranted in intermittent MSUD. Patients and methods We describe eight patients from four unrelated families, diagnosed with intermittent MSUD. Their presenting symptoms during metabolic crises varied from confusion and decreased consciousness, to ataxia, and acute psychosis. Molecular confirmation of MSUD was pursued via sequencing of the BCKDHA, BCKDHB and DBT genes. Results All affected individuals were found to harbor bi-allelic pathogenic variants in either BCKDHB or DBT. Of the seven variants, four variants in BCKDHB (p.G101D, p. V103A, p. A221D, p. Y195C) and one variant in DBT (p.K427E) were not previously described. Conclusions While newborn screening programs allow for early detection of classic MSUD, cases of the intermittent form might go undetected, and present later in childhood following metabolic derailment, with an array of non-specific symptoms. Our experience with the families reported herein adds to the current knowledge regarding the phenotype and mutational spectrum of this unique inborn error of branched-chain amino acid metabolism, and underscore the high index of suspicion required for its diagnosis.
- Published
- 2020
28. Pathogenic Variants in NUP214 Cause 'Plugged' Nuclear Pore Channels and Acute Febrile Encephalopathy
- Author
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Nitzan Biran, Ciro Leonardo Pierri, Somaya Salah, Carolyn D. Applegate, Orly Elpeleg, Boris Fichtman, Tal Gilboa, Giuseppe Punzi, Avraham Shaag, Yuval Salzberg, Ada Hamosh, Nara Sobreira, Houriya Ayoubieh, Amnon Harel, Natalia Simanovsky, Fadia Zagairy, Tamar Harel, and Simon Edvardson
- Subjects
Male ,Protein Conformation ,Active Transport, Cell Nucleus ,Mutation, Missense ,Apoptosis ,Ion Channels ,Article ,Frameshift mutation ,Genetics ,medicine ,Acute Febrile Encephalopathy ,Humans ,Nuclear pore ,Fibroblast ,Child ,Frameshift Mutation ,Genetics (clinical) ,Barrier function ,Cells, Cultured ,Cell Proliferation ,Cell Nucleus ,Chemistry ,Neurodegeneration ,Infant ,Fibroblasts ,medicine.disease ,Cell biology ,Pedigree ,Nuclear Pore Complex Proteins ,medicine.anatomical_structure ,Child, Preschool ,Nuclear Pore ,Female ,Nucleoporin ,Nuclear transport - Abstract
We report biallelic missense and frameshift pathogenic variants in the gene encoding human nucleoporin NUP214 causing acute febrile encephalopathy. Clinical symptoms include neurodevelopmental regression, seizures, myoclonic jerks, progressive microcephaly, and cerebellar atrophy. NUP214 and NUP88 protein levels were reduced in primary skin fibroblasts derived from affected individuals, while the total number and density of nuclear pore complexes remained normal. Nuclear transport assays exhibited defects in the classical protein import and mRNA export pathways in affected cells. Direct surface imaging of fibroblast nuclei by scanning electron microscopy revealed a large increase in the presence of central particles (known as "plugs") in the nuclear pore channels of affected cells. This observation suggests that large transport cargoes may be delayed in passage through the nuclear pore channel, affecting its selective barrier function. Exposure of fibroblasts from affected individuals to heat shock resulted in a marked delay in their stress response, followed by a surge in apoptotic cell death. This suggests a mechanistic link between decreased cell survival in cell culture and severe fever-induced brain damage in affected individuals. Our study provides evidence by direct imaging at the single nuclear pore level of functional changes linked to a human disease.
- Published
- 2018
29. MARS variant associated with both recessive interstitial lung and liver disease and dominant Charcot-Marie-Tooth disease
- Author
-
Anthony Antonellis, Shoshana Revel-Vilk, Shimon Reif, Jonathan Rips, Avraham Shaag, Oded Breuer, Tamar Harel, Rebecca Meyer-Schuman, Reuven Tsabari, and Orly Elpeleg
- Subjects
0301 basic medicine ,Male ,Developmental Disabilities ,Mutation, Missense ,Genes, Recessive ,Methionine-tRNA Ligase ,Saccharomyces cerevisiae ,Biology ,Compound heterozygosity ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Liver disease ,0302 clinical medicine ,Charcot-Marie-Tooth Disease ,Genetics ,medicine ,Humans ,Gene ,Genetics (clinical) ,Exome sequencing ,Genes, Dominant ,Cholestasis ,Aminoacyl tRNA synthetase ,Interstitial lung disease ,Infant ,General Medicine ,Syndrome ,medicine.disease ,Phenotype ,Pedigree ,Complementation ,030104 developmental biology ,chemistry ,Lung Diseases, Interstitial ,030217 neurology & neurosurgery - Abstract
Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for charging tRNA with cognate amino acids during protein translation. Non-canonical functions are increasingly recognized, and include transcription and translation control and extracellular signaling. Monoallelic mutations in genes encoding several ARSs have been identified in axonal Charcot-Marie-Tooth (CMT2) disease, whereas biallelic mutations in ARS loci have been associated with multi-tissue syndromes, variably involving the central nervous system, lung, and liver. We report a male infant of non-consanguineous origin, presenting with successive onset of transfusion-dependent anemia, hypothyroidism, cholestasis, interstitial lung disease, and developmental delay. Whole-exome sequencing (WES) revealed compound heterozygosity for two variants (p.Tyr307Cys and p.Arg618Cys) in MARS, encoding methionyl-tRNA synthetase. Biallelic MARS mutations are associated with interstitial lung and liver disease (ILLD). Interestingly, the p.Arg618Cys variant, inherited from an unaffected father, was previously reported in a family with autosomal dominant late-onset CMT2. Yeast complementation assays confirmed pathogenicity of p.Arg618Cys, yet suggested retained function of p.Tyr307Cys. Our findings underscore the phenotypic variability associated with ARS mutations, and suggest genetic or environmental modifying factors in the onset of monoallelic MARS-associated CMT2.
- Published
- 2018
30. Homozygous mutation in MFSD2A, encoding a lysolipid transporter for docosahexanoic acid, is associated with microcephaly and hypomyelination
- Author
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Orly Elpeleg, Hao Fan, Amaury Cazenave-Gassiot, David L. Silver, Tamar Harel, Dorit Shmueli, Itai Berger, Markus R. Wenk, Shimon Edvardson, Debra Q Y Quek, Avraham Shaag, and Bernice H. Wong
- Subjects
0301 basic medicine ,Male ,Models, Molecular ,medicine.medical_specialty ,Microcephaly ,Docosahexaenoic Acids ,Developmental Disabilities ,Central nervous system ,Mutation, Missense ,Biology ,medicine.disease_cause ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Mice ,Mutant protein ,Internal medicine ,Genetics ,medicine ,Missense mutation ,Animals ,Humans ,Global developmental delay ,Child ,Genetics (clinical) ,Myelin Sheath ,Mice, Knockout ,Mutation ,Symporters ,Siblings ,Tumor Suppressor Proteins ,Neurogenesis ,Homozygote ,Lysophosphatidylcholines ,Biological Transport ,medicine.disease ,Lipid Metabolism ,Hypotonia ,Pedigree ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,HEK293 Cells ,Amino Acid Substitution ,Blood-Brain Barrier ,Child, Preschool ,Female ,medicine.symptom ,Demyelinating Diseases - Abstract
The major facilitator superfamily domain-containing protein 2A (MFSD2A) is a constituent of the blood-brain barrier and functions to transport lysophosphatidylcholines (LPCs) into the central nervous system. LPCs such as that derived from docosahexanoic acid (DHA) are indispensable to neurogenesis and maintenance of neurons, yet cannot be synthesized within the brain and are dependent on MFSD2A for brain uptake. Recent studies have implicated MFSD2A mutations in lethal and non-lethal microcephaly syndromes, with the severity correlating to the residual activity of the transporter. We describe two siblings with shared parental ancestry, in whom we identified a homozygous missense mutation (c.1205C > A; p.Pro402His) in MFSD2A. Both affected individuals had microcephaly, hypotonia, appendicular spasticity, dystonia, strabismus, and global developmental delay. Neuroimaging revealed paucity of white matter with enlarged lateral ventricles. Plasma lysophosphatidylcholine (LPC) levels were elevated, reflecting reduced brain transport. Cell-based studies of the p.Pro402His mutant protein indicated complete loss of activity of the transporter despite the non-lethal, attenuated phenotype. The aggregate data of MFSD2A-associated genotypes and phenotypes suggest that additional factors, such as nutritional supplementation or modifying genetic factors, may modulate the severity of disease and call for consideration of treatment options for affected individuals.
- Published
- 2018
31. Homozygous loss-of-function mutations in MNS1 cause laterality defects and likely male infertility
- Author
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Ibrahim A. Abu Zahira, Stef J.F. Letteboer, Azaria J.J.T. Rein, Alaa Darwish, Zeev Perles, Asaf Ta-Shma, Ronald Roepman, Sabrina Spittler, Avraham Shaag, Christine Edelbusch, Petra Pennekamp, Israel Amirav, Heike Olbrich, Dorus A. Mans, Alper Gezdirici, Nael Elias, Sandra Cindric, Oded Breuer, Miriam Schmidts, Isabella Aprea, Rim Hjeij, Tabea Nöthe-Menchen, Dinu Antony, Heymut Omran, Friederike Stuhlmann, Elif Yilmaz Gulec, Niki T. Loges, Orly Elpeleg, Gerard W. Dougherty, and Revital Abitbul
- Subjects
0301 basic medicine ,Male ,Cancer Research ,Axoneme ,Heart malformation ,Genetic Linkage ,Cell Cycle Proteins ,030105 genetics & heredity ,Ciliopathies ,Functional Laterality ,Male infertility ,Mice ,Child ,Genetics (clinical) ,Genetics ,Mice, Knockout ,Cilium ,Homozygote ,Nuclear Proteins ,Middle Aged ,Pedigree ,Codon, Nonsense ,Child, Preschool ,Motile cilium ,Female ,Infertility ,Adult ,lcsh:QH426-470 ,Adolescent ,Nonsense mutation ,Biology ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Young Adult ,All institutes and research themes of the Radboud University Medical Center ,Exome Sequencing ,medicine ,Animals ,Humans ,Cilia ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,Infertility, Male ,Infant ,Axonemal Dyneins ,medicine.disease ,lcsh:Genetics ,030104 developmental biology ,Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] ,Gene Expression Regulation ,Sperm Tail ,Outer dynein arm - Abstract
The clinical spectrum of ciliopathies affecting motile cilia spans impaired mucociliary clearance in the respiratory system, laterality defects including heart malformations, infertility and hydrocephalus. Using linkage analysis and whole exome sequencing, we identified two recessive loss-of-function MNS1 mutations in five individuals from four consanguineous families: 1) a homozygous nonsense mutation p.Arg242* in four males with laterality defects and infertility and 2) a homozygous nonsense mutation p.Gln203* in one female with laterality defects and recurrent respiratory infections additionally carrying homozygous mutations in DNAH5. Consistent with the laterality defects observed in these individuals, we found Mns1 to be expressed in mouse embryonic ventral node. Immunofluorescence analysis further revealed that MNS1 localizes to the axonemes of respiratory cilia as well as sperm flagella in human. In-depth ultrastructural analyses confirmed a subtle outer dynein arm (ODA) defect in the axonemes of respiratory epithelial cells resembling findings reported in Mns1-deficient mice. Ultrastructural analyses in the female carrying combined mutations in MNS1 and DNAH5 indicated a role for MNS1 in the process of ODA docking (ODA-DC) in the distal respiratory axonemes. Furthermore, co-immunoprecipitation and yeast two hybrid analyses demonstrated that MNS1 dimerizes and interacts with the ODA docking complex component CCDC114. Overall, we demonstrate that MNS1 deficiency in humans causes laterality defects (situs inversus) and likely male infertility and that MNS1 plays a role in the ODA-DC assembly.
- Published
- 2018
32. Severe infantile epileptic encephalopathy associated with D-glyceric aciduria: report of a novel case and review
- Author
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Yoav Zehavi, Avraham Shaag, Sarit Ravid, Ronen Spiegel, Hanna Mandel, Erwin E. W. Jansen, Orly Elpeleg, Ayelet Eran, Muhammad Abu Rashid, Ann Saada, Mirjam M.C. Wamelink, Clinical chemistry, AGEM - Endocrinology, metabolism and nutrition, AGEM - Inborn errors of metabolism, and Amsterdam Neuroscience - Cellular & Molecular Mechanisms
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Corpus callosum ,Glyceric Acids ,Biochemistry ,White matter ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Atrophy ,Internal medicine ,medicine ,Missense mutation ,Humans ,Child ,Exome sequencing ,Progressive microcephaly ,Brain Diseases ,Epilepsy ,business.industry ,Cortical blindness ,Metabolic disorder ,Infant ,medicine.disease ,Phosphotransferases (Alcohol Group Acceptor) ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Phenotype ,Hyperoxaluria, Primary ,Mutation ,Neurology (clinical) ,business ,Spasms, Infantile ,030217 neurology & neurosurgery - Abstract
D-glycerate 2 kinase (DGK) is an enzyme that mediates the conversion of D-glycerate, an intermediate metabolite of serine and fructose metabolism, to 2-phosphoglycerate. Deficiency of DGK leads to accumulation of D-glycerate in various tissues and its massive excretion in urine. D-glyceric aciduria (DGA) is an autosomal recessive metabolic disorder caused by mutations in the GLYCTK gene. The clinical spectrum of DGA is highly variable, ranging from severe progressive infantile encephalopathy to a practically asymptomatic condition. We describe a male patient from a consanguineous Arab family with infantile onset of DGA, characterized by profound psychomotor retardation, progressive microcephaly, intractable seizures, cortical blindness and deafness. Consecutive brain MR imaging showed an evolving brain atrophy, thinning of the corpus callosum and diffuse abnormal white matter signals. Whole exome sequencing identified the homozygous missense variant in the GLYCTK gene [c.455 T > C, NM_145262.3], which affected a highly conserved leucine residue located at a domain of yet unknown function of the enzyme [p.Leu152Pro, NP_660305]. In silico analysis of the variant supported its pathogenicity. A review of the 15 previously reported patients, together with the current one, confirms a clear association between DGA and severe neurological impairment. Yet, future studies of additional patients with DGA are required to better understand the clinical phenotype and pathogenesis.
- Published
- 2017
33. Nemaline body myopathy caused by a novel mutation in troponin T1 (TNNT1 )
- Author
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Markus Schuelke, Talia Dor, Mohannad Daana, Avraham Shaag, Yakov Fellig, Sharon Eylon, Orly Elpeleg, Ulla Najwa Abdulhaq, and Simon Edvardson
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Physiology ,medicine.disease_cause ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Nemaline myopathy ,Physiology (medical) ,medicine ,Myopathy ,Exome sequencing ,Genetics ,Mutation ,Muscle biopsy ,medicine.diagnostic_test ,biology ,Troponin T ,business.industry ,medicine.disease ,Troponin ,Congenital myopathy ,030104 developmental biology ,biology.protein ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Introduction: Nemaline myopathy is a rare disorder characterized by skeletal muscle weakness of varying severity and onset, with the presence of nemaline rods on muscle biopsy. Congenital nemaline body myopathy due to mutations in TNNT1 has hitherto only been described as a result of a single founder mutation in patients of Amish origin and in 2 other individuals with different recessive mutations. Methods: Autozygosity mapping and whole exome sequencing were applied after we identified 9 Palestinian patients from 7 unrelated families who have nemaline myopathy. Results: All patients were homozygous for a novel complex rearrangement of the TNNT1 gene (c.574_577delinsTAGTGCTGT | NM_003283) leading to C-terminal truncation of the protein (p.L203* | NP_003274.3). Their clinical course was remarkable for early respiratory failure and striking stiffness of the cervical spine. Conclusions: This report exemplifies the utility of combining autozygosity mapping and whole exome sequencing and expands the phenotype associated with TNNT1 mutations. Muscle Nerve, 2015
- Published
- 2015
34. Autoimmune lymphoproliferative syndrome-like disease in patients with LRBA mutation
- Author
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Polina Stepensky, Orly Elpeleg, Klaus Warnatz, Shoshana Revel-Vilk, Ute Fischer, Anne Rensing-Ehl, Schafiq Nabhani, Bärbel Keller, Andrea Hönscheid, Michael Gombert, Avraham Shaag, Arndt Borkhardt, Laura Gámez-Díaz, Hani Saleh, and Bodo Grimbacher
- Subjects
Male ,Cytopenia ,business.industry ,Autoimmune Cytopenia ,Autoimmune Lymphoproliferative Syndrome ,Immunology ,Infant ,Apoptosis ,Sequence Analysis, DNA ,medicine.disease ,Fas ligand ,LRBA ,Child, Preschool ,Autoimmune lymphoproliferative syndrome ,Mutation ,medicine ,Humans ,Immunology and Allergy ,Enteropathy ,Child ,business ,Exome ,Immunodeficiency ,Adaptor Proteins, Signal Transducing - Abstract
Mutations in LPS-responsive and beige-like anchor (LRBA) gene were recently described in patients with combined immunodeficiency, enteropathy and autoimmune cytopenia. Here, we extend the clinical and immunological phenotypic spectrum of LRBA associated disorders by reporting on three patients from two unrelated families who presented with splenomegaly and lymphadenopathy, cytopenia, elevated double negative T cells and raised serum Fas ligand levels resembling autoimmune lymphoproliferative syndrome (ALPS) and one asymptomatic patient. Homozygous loss of function mutations in LRBA were identified by whole exome analysis. Similar to ALPS patients, Fas mediated apoptosis was impaired in LRBA deficient patients, while apoptosis in response to stimuli of the intrinsic mitochondria mediated apoptotic pathway was even enhanced. This manuscript illustrates the phenotypic overlap of other primary immunodeficiencies with ALPS-like disorders and strongly underlines the necessity of genetic diagnosis in order to provide early correct diagnosis and subsequent care.
- Published
- 2015
35. Mutations inSLC1A4, encoding the brain serine transporter, are associated with developmental delay, microcephaly and hypomyelination
- Author
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Wendy K. Chung, Motee Al-Ashhab, Nadirah Damseh, Matthias A. Hediger, Barak Yaacov, Alexandre Simonin, Orly Elpeleg, Aida Telegrafi, Julie Neidich, Jane Juusola, John Pappas, Sherri J. Bale, Kyle Retterer, Joseph A. Picoraro, Bassam Abu-Libdeh, Ellen Moran, Kwame Anyane Yeboa, Avraham Shaag, Simon Edvardson, Megan T. Cho, Chaim Jalas, and Joshua Cappell
- Subjects
Amino Acid Transport System ASC ,Male ,Heterozygote ,medicine.medical_specialty ,Microcephaly ,Adolescent ,Developmental Disabilities ,DNA Mutational Analysis ,Population ,Biology ,medicine.disease_cause ,Serine ,Molecular genetics ,Genetics ,medicine ,Humans ,Serine transport ,Child ,610 Medicine & health ,education ,Exome ,Myelin Sheath ,Genetics (clinical) ,chemistry.chemical_classification ,Mutation ,education.field_of_study ,Genetic Carrier Screening ,Biological Transport ,medicine.disease ,Pedigree ,Amino acid ,Cell biology ,HEK293 Cells ,chemistry ,Child, Preschool ,570 Life sciences ,biology ,Female - Abstract
Background L-serine plays an essential role in neuronal development and function. Although a non-essential amino acid, L-serine must be synthesised within the brain because of its poor permeability by the blood–brain barrier. Within the brain, its synthesis is confined to astrocytes, and its shuttle to neuronal cells is performed by a dedicated neutral amino acid transporter, ASCT1. Methods and results Using exome analysis we identified the recessive mutations, p.E256K, p.L315fs, and p.R457W, in SLC1A4 , the gene encoding ASCT1, in patients with developmental delay, microcephaly and hypomyelination; seizure disorder was variably present. When expressed in a heterologous system, the mutations did not affect the protein level at the plasma membrane but abolished or markedly reduced L-serine transport for p.R457W and p.E256K mutations, respectively. Interestingly, p.E256K mutation displayed a lower L-serine and alanine affinity but the same substrate selectivity as wild-type ASCT1. Conclusions The clinical phenotype of ASCT1 deficiency is reminiscent of defects in L-serine biosynthesis. The data underscore that ASCT1 is essential in brain serine transport. The SLC1A4 p.E256K mutation has a carrier frequency of 0.7% in the Ashkenazi-Jewish population and should be added to the carrier screening panel in this community.
- Published
- 2015
36. Severe infantile male encephalopathy is a result of early post-zygoticWDR45somatic mutation
- Author
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Avraham Shaag, Ronen Spiegel, Dani Bercovich, D. Rabinovich, Stavit A. Shalev, Morad Khayat, and Orly Elpeleg
- Subjects
0301 basic medicine ,Genetics ,Zygote ,Encephalopathy ,030105 genetics & heredity ,Biology ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,WDR45 ,medicine ,030217 neurology & neurosurgery ,Genetics (clinical) - Published
- 2016
37. Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood
- Author
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Avraham Shaag, Berivan Baskin, Zöe Powis, Amber Begtrup, Katelyn Payne, Claudia M. Nicolae, Orly Elpeleg, Chitra Prasad, Asuri N. Prasad, Boris Keren, George Lucian Moldovan, Laurie S. Sadler, Caroline Nava, Cyril Mignot, Simon Edvardson, Thomas E. Mullen, and Pankaj B. Agrawal
- Subjects
0301 basic medicine ,Adult ,Male ,Adolescent ,Nucleolus ,18S ,Biology ,Ribosome ,Polymorphism, Single Nucleotide ,Pediatrics ,Promoter Regions ,03 medical and health sciences ,Young Adult ,Genetic ,Report ,Genetics ,RNA polymerase I ,RNA, Ribosomal, 18S ,Humans ,Polymorphism ,Child ,Promoter Regions, Genetic ,Transcription factor ,Genetics (clinical) ,Ribosomal ,Brain Diseases ,Brain ,Neurodegenerative Diseases ,Single Nucleotide ,Ribosomal RNA ,Molecular biology ,Chromatin ,External transcribed spacer ,DNA-Binding Proteins ,030104 developmental biology ,Transcription preinitiation complex ,RNA ,Female ,Atrophy ,Pol1 Transcription Initiation Complex Proteins ,Cell Nucleolus - Abstract
Summary Ribosomal RNA (rRNA) is transcribed from rDNA by RNA polymerase I (Pol I) to produce the 45S precursor of the 28S, 5.8S, and 18S rRNA components of the ribosome. Two transcription factors have been defined for Pol I in mammals, the selectivity factor SL1, and the upstream binding transcription factor (UBF), which interacts with the upstream control element to facilitate the assembly of the transcription initiation complex including SL1 and Pol I. In seven unrelated affected individuals, all suffering from developmental regression starting at 2.5–7 years, we identified a heterozygous variant, c.628G>A in UBTF , encoding p.Glu210Lys in UBF, which occurred de novo in all cases. While the levels of UBF, Ser388 phosphorylated UBF, and other Pol I-related components (POLR1E, TAF1A, and TAF1C) remained unchanged in cells of an affected individual, the variant conferred gain of function to UBF, manifesting by markedly increased UBF binding to the rDNA promoter and to the 5′- external transcribed spacer. This was associated with significantly increased 18S expression, and enlarged nucleoli which were reduced in number per cell. The data link neurodegeneration in childhood with altered rDNA chromatin status and rRNA metabolism.
- Published
- 2017
38. Coexistence of Two Rare Autosomal Recessive Disorders: Activation-Induced Cytidine Deaminase Deficiency and Sjogren-Larsson Syndrome
- Author
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Oded, Shamriz, Vered, Molho-Pessach, Avraham, Shaag, Hagit, Daum, and Polina, Stepensky
- Subjects
Male ,Sjogren-Larsson Syndrome ,Cytidine Deaminase ,Siblings ,Mutation ,Humans ,Child ,Hyper-IgM Immunodeficiency Syndrome - Published
- 2017
39. Mitochondrial complex IV deficiency, caused by mutated COX6B1, is associated with encephalomyopathy, hydrocephalus and cardiomyopathy
- Author
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Orly Elpeleg, Chaya Miller, Ulla Najwa Abdulhag, Devorah Soiferman, Ora Schueler-Furman, Ann Saada, Simon Edvardson, and Avraham Shaag
- Subjects
Male ,Mitochondrial disease ,Cardiomyopathy ,Biology ,medicine.disease_cause ,Article ,Electron Transport Complex IV ,Mitochondrial Encephalomyopathies ,Genetics ,medicine ,Humans ,Cytochrome c oxidase ,Missense mutation ,Muscle, Skeletal ,Genetics (clinical) ,Mutation ,Muscle biopsy ,medicine.diagnostic_test ,Infant, Newborn ,Syndrome ,Fibroblasts ,medicine.disease ,Mitochondria, Muscle ,Complementation ,Hypertropic ,Cancer research ,biology.protein ,Cardiomyopathies ,Hydrocephalus - Abstract
Isolated cytochrome c oxidase (COX) deficiency is a prevalent cause of mitochondrial disease and is mostly caused by nuclear-encoded mutations in assembly factors while rarely by mutations in structural subunits. We hereby report a case of isolated COX deficiency manifesting with encephalomyopathy, hydrocephalus and hypertropic cardiomyopathy due to a missense p.R20C mutation in the COX6B1 gene, which encodes an integral, nuclear-encoded COX subunit. This novel mutation was predicted to be severe in silico. In accord, enzymatic activity was undetectable in muscle and fibroblasts, was severely decreased in lymphocytes and the COX6B1 protein was barely detectable in patient's muscle mitochondria. Complementation with the wild-type cDNA by a lentiviral construct restored COX activity, and mitochondrial function was improved by 5-aminoimidazole-4-carboxamide ribonucleotide, resveratrol and ascorbate in the patient's fibroblasts. We suggest that genetic analysis of COX6B1should be included in the investigation of isolated COX deficiency, including patients with cardiac defects. Initial measurement of COX activity in lymphocytes may be useful as it might circumvent the need for invasive muscle biopsy. The evaluation of ascorbate supplementation to patients with mutated COX6B1 is warranted.
- Published
- 2014
40. Homozygous null variant in CRADD, encoding an adaptor protein that mediates apoptosis, is associated with lissencephaly
- Author
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Amihood Singer, Moshe Gomori, Orly Elpeleg, Avraham Shaag, Nuphar Hacohen, Vardiella Meiner, and Tamar Harel
- Subjects
0301 basic medicine ,Male ,Death Domain Receptor Signaling Adaptor Proteins ,Genetic counseling ,Lissencephaly ,Prenatal diagnosis ,Apoptosis ,Genetic Counseling ,Biology ,Bioinformatics ,Frameshift mutation ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Fetus ,Pregnancy ,Prenatal Diagnosis ,Intellectual disability ,Genetics ,medicine ,Humans ,Exome ,Genetics (clinical) ,Exome sequencing ,Adaptor Proteins, Signal Transducing ,Sanger sequencing ,Homozygote ,Caspase 2 ,CRADD Signaling Adaptor Protein ,medicine.disease ,Magnetic Resonance Imaging ,030104 developmental biology ,symbols ,Female ,030217 neurology & neurosurgery - Abstract
Lissencephaly is a severe malformation of cortical development, most often attributed to abnormalities in neuronal migration. It is associated with a severe prognosis including developmental delay, intellectual disability, and seizures. Lissencephaly can be reliably diagnosed during late gestation by neurosonography or fetal magnetic resonance imaging (MRI). We report two sibling male fetuses who were diagnosed with delayed cortical sulcation highly suggestive of lissencephaly during late pregnancy. After receiving genetic counseling, the parents elected to terminate the pregnancies based on the neuroradiological findings and the associated severe prognosis. Whole exome sequencing (WES) of an affected fetus, and subsequent Sanger sequencing of the second fetus, revealed a homozygous frameshift variant in CRADD, which encodes an adaptor protein that interacts with PIDD and caspase-2 to initiate apoptosis. Biallelic variants in this gene have been recently reported to cause "thin" lissencephaly and intellectual disability. Interestingly, the allegedly healthy father was also found to be homozygous for the variant, prompting evaluation by brain MRI which revealed hypogyration. This study underscores the phenotypic variability of pathogenic variants in CRADD and the challenges of prenatal genetic counseling.
- Published
- 2016
41. De novo GRIN1 mutations: An emerging cause of severe early infantile encephalopathy
- Author
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Rachel Straussberg, Yoav Zehavi, Banan Jabur, Ronen Spiegel, Muhammad Abu Rashid, Orly Elpeleg, Arie Zehavi, Avraham Shaag, and Hanna Mandel
- Subjects
0301 basic medicine ,Developmental Disabilities ,Encephalopathy ,Mutation, Missense ,Nerve Tissue Proteins ,Hyperkinesis ,medicine.disease_cause ,Receptors, N-Methyl-D-Aspartate ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,Intellectual disability ,Genetics ,medicine ,Humans ,Exome ,Genetics (clinical) ,Exome sequencing ,Mutation ,Brain Diseases ,Binding Sites ,biology ,GRIN1 ,General Medicine ,Syndrome ,medicine.disease ,Hypotonia ,030104 developmental biology ,Child, Preschool ,biology.protein ,Etiology ,Muscle Hypotonia ,Female ,medicine.symptom ,Ion Channel Gating ,030217 neurology & neurosurgery - Abstract
De novo GRIN1 mutations have recently been shown to cause severe intellectual disability, hypotonia, hyperkinetic and stereotyped movements, and epilepsy. We report two new cases of severe early onset encephalopathy associated with hyperkinetic and oculogyric-like movements, caused by mutations in the GRIN1 gene; both were identified by whole exome sequencing. One of the patients harbored the novel mutation p.Ser688Tyr and the other patient harbored the p.Gly827Arg mutation, which was previously reported in three patients. In silico studies suggested that the p.Se688Tyr mutation results in disruption of NMDA ligand binding and the p.Gly827Arg mutation results in disrupted gating of the ion channel. Our study highlights the importance of GRIN1 mutations in the etiology of isolated cases of early onset encephalopathy, and the valuable role of whole exome sequencing in identifying these mutations.
- Published
- 2016
42. EP11.03: The impact of late amniocentesis in the chromosomal microarray era
- Author
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Naama Zvi, Simcha Yagel, Hagit Daum, L. Bar-Or, Michal Macarov, Israela Lerer, Michal Gur, N. Yanai, Avital Eilat, Duha Fahham, Nuphar Hacohen, Ayala Frumkin, Vardiella Meiner, S. Shkedi Rafid, A. Szmulewicz, A. Ben-David, Avraham Shaag, Adva Kimchi, Sarit Helman, and M. Nadjari
- Subjects
0301 basic medicine ,030219 obstetrics & reproductive medicine ,Radiological and Ultrasound Technology ,Microarray ,medicine.diagnostic_test ,business.industry ,Obstetrics and Gynecology ,General Medicine ,030105 genetics & heredity ,Bioinformatics ,03 medical and health sciences ,0302 clinical medicine ,Reproductive Medicine ,Amniocentesis ,Medicine ,Radiology, Nuclear Medicine and imaging ,business - Published
- 2018
43. KIF1Cmutations in two families with hereditary spastic paraparesis and cerebellar dysfunction
- Author
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Ali Benomar, Giovanni Stevanin, Alexis Brice, Marion Gaussen, Alexandra Durr, Simon Edvardson, Markus Schuelke, Talya Dor, Ahmed Bouhouche, Naima Bouslam, Yuval Cinnamon, Avraham Shaag, Laure Raymond, and Vincent Meyer
- Subjects
Male ,Adolescent ,Genetic Linkage ,Hereditary spastic paraplegia ,DNA Mutational Analysis ,Molecular Sequence Data ,Nonsense mutation ,Kinesins ,Biology ,Polymorphism, Single Nucleotide ,Consanguinity ,Young Adult ,Cerebellar Diseases ,Genetic linkage ,Genetics ,medicine ,Spastic ,Humans ,Missense mutation ,Amino Acid Sequence ,Spasticity ,Child ,Genetic Association Studies ,Genetics (clinical) ,KIF1A ,Base Sequence ,Infant ,medicine.disease ,Pedigree ,Chromosome 17 (human) ,HEK293 Cells ,Child, Preschool ,Paraparesis, Spastic ,Female ,medicine.symptom - Abstract
Background Hereditary spastic paraparesis (HSP) (syn. Hereditary spastic paraplegia, SPG) are a group of genetic disorders characterised by spasticity of the lower limbs due to pyramidal tract dysfunction. Nearly 60 disease loci have been identified, which include mutations in two genes ( KIF5A and KIF1A ) that encode motor proteins of the kinesin superfamily. Here we report a novel genetic defect in KIF1C of patients with spastic paraparesis and cerebellar dysfunction in two consanguineous families of Palestinian and Moroccan ancestry. Methods and results We performed autozygosity mapping in a Palestinian and classic linkage analysis in a Moroccan family and found a locus on chromosome 17 that had previously been associated with spastic ataxia type 2 (SPAX2, OMIM %611302). Whole-exome sequencing revealed two homozygous mutations in KIF1C that were absent among controls: a nonsense mutation (c.2191C>T, p.Arg731*) that segregated with the disease phenotype in the Palestinian kindred resulted in the entire absence of KIF1C protein from the patient's fibroblasts, and a missense variant (c.505C>T, p.Arg169Trp) affecting a conserved amino acid of the motor domain that was found in the Moroccan kindred. Conclusions Kinesin genes encode a family of cargo/motor proteins and are known to cause HSP if mutated. Here we identified nonsense and missense mutations in a further member of this protein family. The KIF1C mutation is associated with a HSP subtype (SPAX2/SAX2) that combines spastic paraplegia and weakness with cerebellar dysfunction.
- Published
- 2013
44. Isolated truncus arteriosus associated with a mutation in the plexin-D1 gene
- Author
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Polina Stepensky, Shamir Zenvirt, Azaria J.J.T. Rein, Orly Elpeleg, Ciro Leonardo Pierri, Asaf Ta-Shma, and Avraham Shaag
- Subjects
Heart Defects, Congenital ,Male ,Truncus Arteriosus ,congenital, hereditary, and neonatal diseases and abnormalities ,Cell Adhesion Molecules, Neuronal ,Persistent truncus arteriosus ,Semaphorins ,Biology ,Mice ,PLXND1 Gene ,Genetics ,medicine ,Animals ,Humans ,Exome ,Copy-number variation ,Gene ,Genetic Association Studies ,Genetics (clinical) ,Exome sequencing ,Mice, Knockout ,Membrane Glycoproteins ,Infant, Newborn ,Intracellular Signaling Peptides and Proteins ,Chromosome Mapping ,Infant ,Sequence Analysis, DNA ,Middle Aged ,Disease gene identification ,medicine.disease ,Pedigree ,Child, Preschool ,Mutation ,Mutation (genetic algorithm) ,cardiovascular system ,Female ,Signal Transduction - Abstract
Truncus arteriosus accounts for approximately 1% of congenital heart defects and the cause of isolated non-syndromic truncus arteriosus is largely unknown. In order to identify the underlying molecular defect in a consanguineous family with recurrent tuncus arteriosus, homozygosity mapping followed by whole exome sequencing was performed. This resulted in the identification of a homozygous mutation, Arg1299Cys, in the PLXND1 gene. The mutation affected a highly conserved residue, segregated with the disease in the family and was absent from available SNP databases and ethnic matched controls. in silico comparative modeling revealed that the mutation resides in the N-terminal segment of the human plexin-D1 intracellular region which interacts with the catalytic GTPase-activating protein homology region. The mutation likely destabilizes the intracellular region, perturbing its anchoring and catalytic activity. The phenotype in human PLXND1 mutation is closely related to that of knockout mice for PLXND1, its co-receptor neuropilin-1 or its ligand SEMA3C. It is therefore suggested that SEMA3C signaling, propagated through the heterodimer receptor plexin-D1/neuropilin, is important for truncus arteriosus septation. Confirmation of this observation will require the identification of PLXND1 mutations in additional patients. Exome analysis is valuable for molecular investigation of single patients with congenital heart defects in whom chromosomal copy number variants have been excluded.
- Published
- 2013
45. The Thr224Asn mutation in the VPS45 gene is associated with the congenital neutropenia and primary myelofibrosis of infancy
- Author
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Aviram Kogot-Levin, Hamam Ganaiem, Michael Weintraub, Natalia Simanovsky, Orly Elpeleg, Dror Mevorach, Polina Stepensky, Marianne Cowan, Shamir Zenvirt, Avraham Shaag, Arndt Borkhardt, Yackov Berkun, Hani Saleh, Ann Saada, Adi Tabib, Nia J. Bryant, and Ute Fischer
- Subjects
Male ,Neutropenia ,Blotting, Western ,Molecular Sequence Data ,Immunology ,Vesicular Transport Proteins ,Fluorescent Antibody Technique ,Biochemistry ,Consanguinity ,Thrombasthenia ,medicine ,Congenital Bone Marrow Failure Syndromes ,Humans ,Congenital Neutropenia ,Myelofibrosis ,Exome sequencing ,Base Sequence ,business.industry ,Infant, Newborn ,Bone marrow failure ,Infant ,Cell Biology ,Hematology ,medicine.disease ,Pancytopenia ,Pedigree ,medicine.anatomical_structure ,Primary Myelofibrosis ,Mutation ,Female ,Bone marrow ,business - Abstract
Severe congenital neutropenia as well as primary myelofibrosis are rare in infancy. Elucidation of the underlying mechanism is important because it extends our understanding of the more common adult forms of these disorders. Using homozygosity mapping followed by exome sequencing, we identified a Thr224Asn mutation in the VPS45 gene in infants from consanguineous families who suffered from life-threatening neutropenia, which was refractory to granulocyte CSF, from defective platelet aggregation and myelofibrosis. The mutation segregated in the families, was not present in controls, affected a highly conserved codon, and apparently destabilized the Vps45 protein, which was reduced in the patients' leukocytes. Introduction of the corresponding mutation into yeast resulted in reduced cellular levels of Vps45 and also of the cognate syntaxin Tlg2, which is required for membrane traffic through the endosomal system. A defect in the endosomal-lysosomal pathway, the homologous system in humans, was suggested by the absence of lysosomes in the patients' fibroblasts and by the depletion of α granules in their platelets. Importantly, accelerated apoptosis was observed in the patients' neutrophils and bone marrow. This is the first report of a Vps45-related disease in humans, manifesting by neutropenia, thrombasthenia, myelofibrosis, and progressive bone marrow failure.
- Published
- 2013
46. Early infantile epileptic encephalopathy associated with a high voltage gated calcium channelopathy
- Author
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Shimrit Oz, Nathan Dascal, Fida Aziz Abulhijaa, Shamir Zenvirt, Orly Elpeleg, Avraham Shaag, Flora Barghouthi Taher, and Simon Edvardson
- Subjects
Male ,medicine.medical_specialty ,P-type calcium channel ,Protein subunit ,Blotting, Western ,Mutant ,chemistry.chemical_element ,Biology ,Calcium ,medicine.disease_cause ,Xenopus laevis ,Channelopathy ,Internal medicine ,Genetics ,medicine ,Animals ,Humans ,Child ,Genetics (clinical) ,Mutation ,Voltage-dependent calcium channel ,Voltage-gated ion channel ,medicine.disease ,Molecular biology ,Recombinant Proteins ,Endocrinology ,chemistry ,Child, Preschool ,Oocytes ,Channelopathies ,Female ,Calcium Channels - Abstract
Background Early infantile epileptic encephalopathies usually manifest as severely impaired cognitive and motor development and often result in a devastating permanent global developmental delay and intellectual disability. A large set of genes has been implicated in the aetiology of this heterogeneous group of disorders. Among these, the ion channelopathies play a prominent role. In this study, we investigated the genetic cause of infantile epilepsy in three affected siblings. Methods and results Homozygosity mapping in DNA samples followed by exome analysis in one of the patients resulted in the identification of a homozygous mutation, p.L1040P, in the CACNA2D2 gene. This gene encodes the auxiliary α 2 δ2 subunit of high voltage gated calcium channels. The expression of the α 2 δ2-L1040P mutant instead of α 2 δ2 wild-type (WT) in Xenopus laevis oocytes was associated with a notable reduction of current density of both N (Ca V 2.2) and L (Ca V 1.2) type calcium channels. Western blot and confocal imaging analyses showed that the α 2 δ2-L1040P mutant was synthesised normally in oocyte but only the α 2 δ2-WT, and not the α 2 δ2-L1040P mutant, increased the expression of α 1B , the pore forming subunit of Ca V 2.2, at the plasma membrane. The expression of α 2 δ2-WT with Ca V 2.2 increased the surface expression of α 1B 2.5–3 fold and accelerated current inactivation, whereas α 2 δ2-L1040P did not produce any of these effects. Conclusions L1040P mutation in the CACNA2D2 gene is associated with dysfunction of α 2 δ2, resulting in reduced current density and slow inactivation in neuronal calcium channels. The prolonged calcium entry during depolarisation and changes in surface density of calcium channels caused by deficient α 2 δ2 could underlie the epileptic phenotype. This is the first report of an encephalopathy caused by mutation in the auxiliary α 2 δ subunit of high voltage gated calcium channels in humans, illustrating the importance of this subunit in normal physiology of the human brain.
- Published
- 2013
47. CD59 deficiency is associated with chronic hemolysis and childhood relapsing immune-mediated polyneuropathy
- Author
-
Malcolm Rabie, Yoram Nevo, Zamir Shorer, Shamir Zenvirt, Hanoch Goldshmidt, Sharon Aharoni, Orly Elpeleg, Yair Anikster, Bruria Ben-Zeev, Adi Tabib, Dror Mevorach, Aviva Fattal-Valevski, Yakov Fellig, Avraham Shaag, Asaf Ta-Shma, and Rachel Straussberg
- Subjects
Male ,Anemia, Hemolytic ,Molecular Sequence Data ,Immunology ,Mutation, Missense ,CD59 Antigens ,Hemoglobinuria ,chemical and pharmacologic phenomena ,Libya ,CD59 ,Biochemistry ,Demyelinating disease ,medicine ,Humans ,Point Mutation ,Missense mutation ,Amino Acid Sequence ,Age of Onset ,business.industry ,Point mutation ,Infant ,Membrane Proteins ,Polyradiculoneuropathy ,Cell Biology ,Hematology ,medicine.disease ,Founder Effect ,Hemolysis ,Pedigree ,Morocco ,Protein Transport ,Polyradiculoneuropathy, Chronic Inflammatory Demyelinating ,Child, Preschool ,Jews ,Paroxysmal nocturnal hemoglobinuria ,Female ,business ,Polyneuropathy - Abstract
CD59 deficiency is a common finding in RBCs and WBCs in patients with chronic hemolysis suffering from paroxysmal nocturnal hemoglobinuria in which the acquired mutation in the PIGA gene leads to membrane loss of glycosylphosphatidylinositol-anchored membrane proteins, including CD59. The objective of the present study was to elucidate the molecular basis of childhood familial chronic Coombs-negative hemolysis and relapsing polyneuropathy presenting as chronic inflammatory demyelinating polyradiculoneuropathy in infants of North-African Jewish origin from 4 unrelated families. A founder mutation was searched for using homozygosity mapping followed by exome sequencing. The expression of CD59, CD55, and CD14 was examined in blood cells by flow cytometry followed by Western blot of the CD59 protein. A homozygous missense mutation, p.Cys89Tyr in CD59, was identified in all patients. The mutation segregated with the disease in the families and had a carrier rate of 1:66 among Jewish subjects of North-African origin. The mutated protein was present in the patients' cells in reduced amounts and was undetectable on the membrane surface. Based on the results of the present study, we conclude that the Cys89Tyr mutation in CD59 is associated with a failure of proper localization of the CD59 protein in the cell surface. This mutation is manifested clinically in infancy by chronic hemolysis and relapsing peripheral demyelinating disease.
- Published
- 2013
48. West syndrome caused byST3Gal-IIIdeficiency
- Author
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Raimo Tanzi, Anna-Maria Baumann, Rita Gerardy-Schahn, Orly Elpeleg, Oliver Stephan, Martina Mühlenhoff, Andreas W. Kuss, Avraham Shaag, Shamir Zenvirt, Simon Edvardson, and Liqun He
- Subjects
Genetics ,chemistry.chemical_classification ,Sialyltransferase ,West Syndrome ,Biology ,Disease gene identification ,Hypsarrhythmia ,Epitope ,Neurology ,chemistry ,Forebrain ,medicine ,biology.protein ,Neurology (clinical) ,medicine.symptom ,Glycoprotein ,Exome sequencing - Abstract
Summary West syndrome consists of infantile spasms, hypsarrhythmia, and developmental arrest. Most patients remain mentally retarded and many develop Lennox-Gastaut syndrome. Using homozygosity mapping followed by exome sequencing we identified an ST3GAL3 mutation in three infants with West syndrome. ST3GAL3 encodes a sialyltransferase involved in the biosynthesis of sialyl-Lewis epitopes on cell surface–expressed glycoproteins. The mutation affected an essential sialyl-motif and abolished enzymatic activity. Abnormalities in proteins involved in forebrain γ-aminobutyric acid (GABA)ergic synaptic growth and function were recently proposed to account for infantile spasms. Dysfunctional ST3GAL3 may thus result in perturbation of the posttranslational sialylation of proteins in these pathways.
- Published
- 2012
49. Deficiency of HTRA2/Omi is associated with infantile neurodegeneration and 3-methylglutaconic aciduria
- Author
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Hanna Mandel, Avraham Shaag, Orly Elpeleg, Euvgeni Vlodavsky, Shotaro Saita, Chaim Jalas, Thomas Langer, Dorit Goldsher, and Simon Edvardson
- Subjects
0301 basic medicine ,High-Temperature Requirement A Serine Peptidase 2 ,Male ,DNA Mutational Analysis ,Apoptosis ,Mitochondrion ,Biology ,Mitochondrial Proteins ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Fatal Outcome ,Genetics ,medicine ,Animals ,Humans ,Exome ,Genetics (clinical) ,Neurodegeneration ,Serine Endopeptidases ,Infant, Newborn ,Infant ,Neurodegenerative Diseases ,Syndrome ,3-Methylglutaconic Aciduria ,medicine.disease ,XIAP ,Ubiquitin ligase ,Mitochondria ,Pedigree ,030104 developmental biology ,Biochemistry ,Knockout mouse ,Mutation ,biology.protein ,Cancer research ,Female ,030217 neurology & neurosurgery ,Metabolism, Inborn Errors - Abstract
Background Cell survival critically depends on the integrity of mitochondria, which play a pivotal role during apoptosis. Extensive mitochondrial damage promotes release of pro-apoptotic factors from the intermembrane space of mitochondria. Released mitochondrial proteins include Smac/DIABLO and HTRA2/Omi, which inhibit the cytosolic E3 ubiquitin ligase XIAP and other inhibitors of apoptosis proteins. Aims Here we investigated the cause of extreme hypertonia at birth, alternating with hypotonia, with the subsequent appearance of extrapyramidal symptoms, lack of psychomotor development, microcephaly, intractable seizures and early death in four patients from two unrelated families. The patients showed lactic acidemia, 3-methylglutaconic aciduria, intermittent neutropenia, evolving brain atrophy and disturbed cristae structure in muscle mitochondria. Methods and results Using whole-exome sequencing, we identified missplicing mutation and a 5 bp deletion in HTRA2 , encoding HTRA2/Omi. This protein was completely absent from the patients9 fibroblasts, whose growth was impaired and which were hypersensitive to apoptosis. Expression of HtrA2/Omi or of the proteolytically inactive HTRA2/Omi protein restored the cells9 apoptotic resistance. However, cell growth was only restored by the proteolytically active protein. Conclusions This is the first report of recessive deleterious mutations in HTRA2 in human. The clinical phenotype, the increased apoptotic susceptibility and the impaired cell growth recapitulate those observed in the Htra2 knockout mice and in mutant mice with proteolytically inactive HTRA2/Omi. Together, they underscore the importance of both chaperone and proteolytic activities of HTRA2/Omi for balanced apoptosis sensitivity and for brain development. Absence of HTRA2/Omi is associated with severe neurodegenerative disorder of infancy, abnormal mitochondria, 3-methylglutaconic aciduria and increased sensitivity to apoptosis.
- Published
- 2016
50. Novel Homozygous Missense Mutation in SPG20 Gene Results in Troyer Syndrome Associated with Mitochondrial Cytochrome c Oxidase Deficiency
- Author
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Avraham Shaag, Orly Elpeleg, Devorah Soiferman, Ronen Spiegel, Stavit A. Shalev, and Ann Saada
- Subjects
0301 basic medicine ,Hereditary spastic paraplegia ,Skeletal muscle ,Biology ,Mitochondrion ,medicine.disease ,Molecular biology ,Article ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Mitochondrial respiratory chain ,medicine.anatomical_structure ,medicine ,biology.protein ,Missense mutation ,Cytochrome c oxidase ,030217 neurology & neurosurgery ,Exome sequencing ,Loss function - Abstract
Troyer syndrome is an autosomal recessive form of hereditary spastic paraplegia (HSP) caused by deleterious mutations in the SPG20 gene. Although the disease is associated with a loss of function mechanism of spartin, the protein encoded by SPG20, the precise pathogenesis is yet to be elucidated. Recent data indicated an important role for spartin in both mitochondrial maintenance and function. Here we report a child presenting with progressive spastic paraparesis, generalized muscle weakness, dysarthria, impaired growth, and severe isolated decrease in muscle cytochrome c oxidase (COX) activity. Whole exome sequencing identified the homozygous c.988A>G variant in SPG20 gene (p.Met330Val) resulting in almost complete loss of spartin in skeletal muscle. Further analyses demonstrated significant tissue specific reduction of COX 4, a nuclear encoded subunit of COX, in muscle suggesting a role for spartin in proper mitochondrial respiratory chain function mediated by COX activity. Our findings need to be verified in other Troyer syndrome patients in order to classify it as a form of HSP caused by mitochondrial dysfunction.
- Published
- 2016
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