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12 results on '"Conceicao, Bettencourt"'

1. Epigenome-wide association study of peripheral immune cell populations in Parkinson’s disease

Author

Maren Stolp Andersen, Ingvild Sørum Leikfoss, Ina Skaara Brorson, Chiara Cappelletti, Conceicao Bettencourt, Mathias Toft, and Lasse Pihlstrøm

Subjects
Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Understanding the contribution of immune mechanisms to Parkinson’s disease pathogenesis is an important challenge, potentially of major therapeutic implications. To further elucidate the involvement of peripheral immune cells, we studied epigenome-wide DNA methylation in isolated populations of CD14+ monocytes, CD19+ B cells, CD4+ T cells, and CD8+ T cells from Parkinson’s disease patients and healthy control participants. We included 25 patients with a maximum five years of disease duration and 25 controls, and isolated four immune cell populations from each fresh blood sample. Epigenome-wide DNA methylation profiles were generated from 186 samples using the Illumina MethylationEpic array and association with disease status was tested using linear regression models. We identified six differentially methylated CpGs in CD14+ monocytes and one in CD8 + T cells. Four differentially methylated regions were identified in monocytes, including a region upstream of RAB32, a gene that has been linked to LRRK2. Methylation upstream of RAB32 correlated negatively with mRNA expression, and RAB32 expression was upregulated in Parkinson’s disease both in our samples and in summary statistics from a previous study. Our epigenome-wide association study of early Parkinson’s disease provides evidence for methylation changes across different peripheral immune cell types, highlighting monocytes and the RAB32 locus. The findings were predominantly cell-type-specific, demonstrating the value of isolating purified cell populations for genomic studies.

Published
2023
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3. Differential LRRK2 Signalling and Gene Expression in WT-LRRK2 and G2019S-LRRK2 Mouse Microglia Treated with Zymosan and MLi2

Author

Iqra Nazish, Adamantios Mamais, Anna Mallach, Conceicao Bettencourt, Alice Kaganovich, Thomas Warner, John Hardy, Patrick A. Lewis, Jennifer Pocock, Mark R. Cookson, and Rina Bandopadhyay

Subjects
LRRK2, TLR2, LRRK2 p.G2019S knock-in, zymosan, MLi.2, RNA-Seq, Cytology, QH573-671
Abstract

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause autosomal dominant Parkinson’s disease (PD), with the most common causative mutation being the LRRK2 p.G2019S within the kinase domain. LRRK2 protein is highly expressed in the human brain and also in the periphery, and high expression of dominant PD genes in immune cells suggests involvement of microglia and macrophages in inflammation related to PD. LRRK2 is known to respond to extracellular signalling including TLR4, resulting in alterations in gene expression, with the response to TLR2 signalling through zymosan being less known. Here, we investigated the effects of zymosan, a TLR2 agonist and the potent and specific LRRK2 kinase inhibitor MLi-2 on gene expression in microglia from LRRK2-WT and LRRK2 p.G2019S knock-in mice by RNA-sequencing analysis. We observed both overlapping and distinct zymosan and MLi-2 mediated gene expression profiles in microglia. At least two candidate genome-wide association (GWAS) hits for PD, CathepsinB (Ctsb) and Glycoprotein-nmb (Gpnmb), were notably downregulated by zymosan treatment. Genes involved in inflammatory response and nervous system development were up and downregulated, respectively, with zymosan treatment, while MLi-2 treatment particularly exhibited upregulated genes for ion transmembrane transport regulation. Furthermore, we observed that the top twenty most significantly differentially expressed genes in LRRK2 p.G2019S microglia show enriched biological processes in iron transport and response to oxidative stress. Overall, these results suggest that microglial LRRK2 may contribute to PD pathogenesis through altered inflammatory pathways. Our findings should encourage future investigations of these putative avenues in the context of PD pathogenesis.

Published
2023
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4. Creating connections: developing an online space for cross-regional mentorship and network building in the dementia research field [version 2; peer review: 2 approved]

Author

Michael Daniels, Adam Smith, Conceicao Bettencourt, Susan Simpson, Fiona Mclean, Fiona Kerr, Nathan Woodling, and Josie Fullerton

Subjects
mentoring, mentorship, early career researchers, dementia, Alzheimer’s disease, eng, Medicine
Abstract

Background Effective development and retention of talented early-career researchers (ECRs) is essential to the continued success of biomedical science research fields. To this end, formal mentorship programmes (where researchers are paired with one or more mentors beyond their direct manager) have proven to be successful in providing support and expanding career development opportunities. However, many programmes are limited to pools of mentors and mentees within one institute or geographical area, highlighting that cross-regional connections may be a missed opportunity in many mentorship schemes. Methods Here, we aimed to address this limitation through our pilot cross-regional mentorship scheme, creating reciprocal mentor-mentee pairings between two pre-established networks of Alzheimer’s Research UK (ARUK) Network-associated researchers. We carefully created 21 mentor-mentee pairings between the Scotland and University College London (UCL) networks in 2021, with surveys conducted to assess mentor/mentee satisfaction with the programme. Results Participants reported very high satisfaction with the nature of the pairings and the mentors’ contribution to the career development of mentees; a majority also reported that the mentorship scheme increased their connections outside of their home network. Our assessment of this pilot programme is that it supports the utility of cross-regional mentorship schemes for ECR development. At the same time, we highlight the limitations of our programme and recommend areas for improvement in future programmes, including greater consideration of support for minoritized groups and the need for additional training for mentors. Conclusions In conclusion, our pilot scheme generated successful and novel mentor-mentee pairings across pre-existing networks; both of which reported high satisfaction with pairings, ECR career and personal development, and the formation of new cross-network connections. This pilot may serve as a model for other networks of biomedical researchers, where existing networks within medical research charities can act as a scaffold to build new cross-regional career development opportunities for researchers.

Published
2023
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5. Transcriptional profiling of multiple system atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease

Author

Ignazio S. Piras, Christiane Bleul, Isabelle Schrauwen, Joshua Talboom, Lorida Llaci, Matthew D. De Both, Marcus A. Naymik, Glenda Halliday, Conceicao Bettencourt, Janice L. Holton, Geidy E. Serrano, Lucia I. Sue, Thomas G. Beach, Nadia Stefanova, and Matthew J. Huentelman

Subjects
Multiple system atrophy, RNA sequencing, Oligodendrocytes, Neurodegeneration, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Multiple system atrophy (MSA) is a rare adult-onset neurodegenerative disease of unknown cause, with no effective therapeutic options, and no cure. Limited work to date has attempted to characterize the transcriptional changes associated with the disease, which presents as either predominating parkinsonian (MSA-P) or cerebellar (MSC-C) symptoms. We report here the results of RNA expression profiling of cerebellar white matter (CWM) tissue from two independent cohorts of MSA patients (n = 66) and healthy controls (HC; n = 66). RNA samples from bulk brain tissue and from oligodendrocytes obtained by laser capture microdissection (LCM) were sequenced. Differentially expressed genes (DEGs) were obtained and were examined before and after stratifying by MSA clinical sub-type. We detected the highest number of DEGs in the MSA-C group (n = 747) while only one gene was noted in MSA-P, highlighting the larger dysregulation of the transcriptome in the MSA-C CWM. Results from both bulk tissue and LCM analysis showed a downregulation of oligodendrocyte genes and an enrichment for myelination processes with a key role noted for the QKI gene. Additionally, we observed a significant upregulation of neuron-specific gene expression in MSA-C and enrichment for synaptic processes. A third cluster of genes was associated with the upregulation of astrocyte and endothelial genes, two cell types with a key role in inflammation processes. Finally, network analysis in MSA-C showed enrichment for β-amyloid related functional classes, including the known Alzheimer’s disease (AD) genes, APP and PSEN1. This is the largest RNA profiling study ever conducted on post-mortem brain tissue from MSA patients. We were able to define specific gene expression signatures for MSA-C highlighting the different stages of the complex neurodegenerative cascade of the disease that included alterations in several cell-specific transcriptional programs. Finally, several results suggest a common transcriptional dysregulation between MSA and AD-related genes despite the clinical and neuropathological distinctions between the two diseases.

Published
2020
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6. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Author

Vincenzo Salpietro, Christine L. Dixon, Hui Guo, Oscar D. Bello, Jana Vandrovcova, Stephanie Efthymiou, Reza Maroofian, Gali Heimer, Lydie Burglen, Stephanie Valence, Erin Torti, Moritz Hacke, Julia Rankin, Huma Tariq, Estelle Colin, Vincent Procaccio, Pasquale Striano, Kshitij Mankad, Andreas Lieb, Sharon Chen, Laura Pisani, Conceicao Bettencourt, Roope Männikkö, Andreea Manole, Alfredo Brusco, Enrico Grosso, Giovanni Battista Ferrero, Judith Armstrong-Moron, Sophie Gueden, Omer Bar-Yosef, Michal Tzadok, Kristin G. Monaghan, Teresa Santiago-Sim, Richard E. Person, Megan T. Cho, Rebecca Willaert, Yongjin Yoo, Jong-Hee Chae, Yingting Quan, Huidan Wu, Tianyun Wang, Raphael A. Bernier, Kun Xia, Alyssa Blesson, Mahim Jain, Mohammad M. Motazacker, Bregje Jaeger, Amy L. Schneider, Katja Boysen, Alison M. Muir, Candace T. Myers, Ralitza H. Gavrilova, Lauren Gunderson, Laura Schultz-Rogers, Eric W. Klee, David Dyment, Matthew Osmond, Mara Parellada, Cloe Llorente, Javier Gonzalez-Peñas, Angel Carracedo, Arie Van Haeringen, Claudia Ruivenkamp, Caroline Nava, Delphine Heron, Rosaria Nardello, Michele Iacomino, Carlo Minetti, Aldo Skabar, Antonella Fabretto, SYNAPS Study Group, Miquel Raspall-Chaure, Michael Chez, Anne Tsai, Emily Fassi, Marwan Shinawi, John N. Constantino, Rita De Zorzi, Sara Fortuna, Fernando Kok, Boris Keren, Dominique Bonneau, Murim Choi, Bruria Benzeev, Federico Zara, Heather C. Mefford, Ingrid E. Scheffer, Jill Clayton-Smith, Alfons Macaya, James E. Rothman, Evan E. Eichler, Dimitri M. Kullmann, and Henry Houlden

Subjects
Science
Abstract

Genetic variants in ionotropic glutamate receptors have been implicated in neurodevelopmental disorders. Here, the authors report heterozygous de novo mutations in the GRIA2 gene in 28 individuals with intellectual disability and neurodevelopmental abnormalities associated with reduced Ca2+ transport and AMPAR currents.”

Published
2019
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8. Additional file 1 of Transcriptional profiling of multiple system atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease

Author

Piras, Ignazio S., Bleul, Christiane, Schrauwen, Isabelle, Talboom, Joshua, Llaci, Lorida, Both, Matthew D. De, Naymik, Marcus A., Halliday, Glenda, Conceicao Bettencourt, Holton, Janice L., Geidy E. Serrano, Sue, Lucia I., Beach, Thomas G., Stefanova, Nadia, and Huentelman, Matthew J.

Abstract

Additional file 1 Supplementary Appendix. Supplementary Methods. Supplementary Results. Figure S1. PCA analysis conducted on cohort 1 after transformation of the raw counts using regularized log2 transformation. Samples were labeled by diagnostic status. No significant outliers were detected. The final sample size was: MSA = 19, HC = 19. Figure S2. PCA analysis conducted on cohort 2 after transformation of the raw counts using regularized log2 transformation. Samples were labeled by diagnostic status. One outlier was identified (A) and removed (B). The final sample size was: MSA = 47; HC = 47. Figure S3. PCA analysis conducted on oligodendrocytes LCM data from cohort 1 after transformation of the raw counts using regularized log2 transformation. Samples were labeled by diagnostic status. Three extreme outliers were identified (A) and removed (B). The final sample size was: MSA = 4; HC = 5. Figure S4. Number of differentially expressed genes (adj p 0.204; p

Published
2020
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9. AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Author

Vincenzo, Salpietro, Christine L, Dixon, Hui, Guo, Oscar D, Bello, Jana, Vandrovcova, Stephanie, Efthymiou, Reza, Maroofian, Gali, Heimer, Lydie, Burglen, Stephanie, Valence, Erin, Torti, Moritz, Hacke, Julia, Rankin, Huma, Tariq, Estelle, Colin, Vincent, Procaccio, Pasquale, Striano, Kshitij, Mankad, Andreas, Lieb, Sharon, Chen, Laura, Pisani, Conceicao, Bettencourt, Roope, Männikkö, Andreea, Manole, Alfredo, Brusco, Enrico, Grosso, Giovanni Battista, Ferrero, Judith, Armstrong-Moron, Sophie, Gueden, Omer, Bar-Yosef, Michal, Tzadok, Kristin G, Monaghan, Teresa, Santiago-Sim, Richard E, Person, Megan T, Cho, Rebecca, Willaert, Yongjin, Yoo, Jong-Hee, Chae, Yingting, Quan, Huidan, Wu, Tianyun, Wang, Raphael A, Bernier, Kun, Xia, Alyssa, Blesson, Mahim, Jain, Mohammad M, Motazacker, Bregje, Jaeger, Amy L, Schneider, Katja, Boysen, Alison M, Muir, Candace T, Myer, Ralitza H, Gavrilova, Lauren, Gunderson, Laura, Schultz-Roger, Eric W, Klee, David, Dyment, Matthew, Osmond, Mara, Parellada, Cloe, Llorente, Javier, Gonzalez-Peña, Angel, Carracedo, Arie, Van Haeringen, Claudia, Ruivenkamp, Caroline, Nava, Delphine, Heron, Rosaria, Nardello, Michele, Iacomino, Carlo, Minetti, Aldo, Skabar, Antonella, Fabretto, Hanna, Michael G., Bugiardini, Enrico, Hostettler, Isabel, O’Callaghan, Benjamin, Khan, Alaa, Cortese, Andrea, O’Connor, Emer, Yau, Wai Y., Bourinaris, Thoma, Kaiyrzhanov, Rauan, Chelban, Viorica, Madej, Monika, Diana, Maria C., Vari, Maria S., Pedemonte, Marina, Bruno, Claudio, Balagura, Ganna, Scala, Marcello, Fiorillo, Chiara, Nobili, Lino, Malintan, Nancy T., Zanetti, Maria N., Krishnakumar, Shyam S., Lignani, Gabriele, Jepson, James E. C., Broda, Paolo, Baldassari, Simona, Rossi, Pia, Fruscione, Floriana, Madia, Francesca, Traverso, Monica, De-Marco, Patrizia, Pérez-Dueñas, Belen, Munell, Francina, Kriouile, Yamna, El-Khorassani, Mohamed, Karashova, Blagovesta, Avdjieva, Daniela, Kathom, Hadil, Tincheva, Radka, Van-Maldergem, Lionel, Nachbauer, Wolfgang, Boesch, Sylvia, Gagliano, Antonella, Amadori, Elisabetta, Goraya, Jatinder S., Sultan, Tipu, Kirmani, Salman, Ibrahim, Shahnaz, Jan, Farida, Mine, Jun, Banu, Selina, Veggiotti, Pierangelo, Zuccotti, Gian V., Ferrari, Michel D., Van Den Maagdenberg, Arn M. J., Verrotti, Alberto, Marseglia, Gian L., Savasta, Salvatore, Soler, Miguel A., Scuderi, Carmela, Borgione, Eugenia, Chimenz, Roberto, Gitto, Eloisa, Dipasquale, Valeria, Sallemi, Alessia, Fusco, Monica, Cuppari, Caterina, Cutrupi, Maria C., Ruggieri, Martino, Cama, Armando, Capra, Valeria, Mencacci, Niccolò E., Boles, Richard, Gupta, Neerja, Kabra, Madhulika, Papacostas, Savva, Zamba-Papanicolaou, Eleni, Dardiotis, Efthymio, Maqbool, Shazia, Rana, Nuzhat, Atawneh, Osama, Lim, Shen Y., Shaikh, Farooq, Koutsis, George, Breza, Marianthi, Coviello, Domenico A., Dauvilliers, Yves A., Alkhawaja, Issam, Alkhawaja, Mariam, Al-Mutairi, Fuad, Stojkovic, Tanya, Ferrucci, Veronica, Zollo, Massimo, Alkuraya, Fowzan S., Kinali, Maria, Sherifa, Hamed, Benrhouma, Hanene, Turki, Ilhem B. Y., Tazir, Meriem, Obeid, Makram, Bakhtadze, Sophia, Saadi, Nebal W., Zaki, Maha S., Triki, Chahnez C., Benfenati, Fabio, Gustincich, Stefano, Kara, Majdi, Belcastro, Vincenzo, Specchio, Nicola, Capovilla, Giuseppe, Karimiani, Ehsan G., Salih, Ahmed M., Okubadejo, Njideka U., Ojo, Oluwadamilola O., Oshinaike, Olajumoke O., Oguntunde, Olapeju, Wahab, Kolawole, Bello, Abiodun H., Abubakar, Sanni, Obiabo, Yahaya, Nwazor, Ernest, Ekenze, Oluchi, Williams, Uduak, Iyagba, Alagoma, Taiwo, Lolade, Komolafe, Morenikeji, Senkevich, Konstantin, Shashkin, Chingiz, Zharkynbekova, Nazira, Koneyev, Kairgali, Manizha, Ganieva, Isrofilov, Maksud, Guliyeva, Ulviyya, Salayev, Kamran, Khachatryan, Samson, Rossi, Salvatore, Silvestri, Gabriella, Haridy, Nourelhoda, Ramenghi, Luca A., Xiromerisiou, Georgia, David, Emanuele, Aguennouz, Mhammed, Fidani, Liana, Spanaki &amp, Cleanthe, Tucci, Arianna, Miquel, Raspall-Chaure, Michael, Chez, Anne, Tsai, Emily, Fassi, Marwan, Shinawi, John N, Constantino, Rita, De Zorzi, Sara, Fortuna, Fernando, Kok, Boris, Keren, Dominique, Bonneau, Murim, Choi, Bruria, Benzeev, Federico, Zara, Heather C, Mefford, Ingrid E, Scheffer, Jill, Clayton-Smith, Alfons, Macaya, James E, Rothman, Evan E, Eichler, Dimitri M, Kullmann, Henry, Houlden, Salvatore Rossi, Gabriella Silvestri (ORCID:0000-0002-1950-1468), Vincenzo, Salpietro, Christine L, Dixon, Hui, Guo, Oscar D, Bello, Jana, Vandrovcova, Stephanie, Efthymiou, Reza, Maroofian, Gali, Heimer, Lydie, Burglen, Stephanie, Valence, Erin, Torti, Moritz, Hacke, Julia, Rankin, Huma, Tariq, Estelle, Colin, Vincent, Procaccio, Pasquale, Striano, Kshitij, Mankad, Andreas, Lieb, Sharon, Chen, Laura, Pisani, Conceicao, Bettencourt, Roope, Männikkö, Andreea, Manole, Alfredo, Brusco, Enrico, Grosso, Giovanni Battista, Ferrero, Judith, Armstrong-Moron, Sophie, Gueden, Omer, Bar-Yosef, Michal, Tzadok, Kristin G, Monaghan, Teresa, Santiago-Sim, Richard E, Person, Megan T, Cho, Rebecca, Willaert, Yongjin, Yoo, Jong-Hee, Chae, Yingting, Quan, Huidan, Wu, Tianyun, Wang, Raphael A, Bernier, Kun, Xia, Alyssa, Blesson, Mahim, Jain, Mohammad M, Motazacker, Bregje, Jaeger, Amy L, Schneider, Katja, Boysen, Alison M, Muir, Candace T, Myer, Ralitza H, Gavrilova, Lauren, Gunderson, Laura, Schultz-Roger, Eric W, Klee, David, Dyment, Matthew, Osmond, Mara, Parellada, Cloe, Llorente, Javier, Gonzalez-Peña, Angel, Carracedo, Arie, Van Haeringen, Claudia, Ruivenkamp, Caroline, Nava, Delphine, Heron, Rosaria, Nardello, Michele, Iacomino, Carlo, Minetti, Aldo, Skabar, Antonella, Fabretto, Hanna, Michael G., Bugiardini, Enrico, Hostettler, Isabel, O’Callaghan, Benjamin, Khan, Alaa, Cortese, Andrea, O’Connor, Emer, Yau, Wai Y., Bourinaris, Thoma, Kaiyrzhanov, Rauan, Chelban, Viorica, Madej, Monika, Diana, Maria C., Vari, Maria S., Pedemonte, Marina, Bruno, Claudio, Balagura, Ganna, Scala, Marcello, Fiorillo, Chiara, Nobili, Lino, Malintan, Nancy T., Zanetti, Maria N., Krishnakumar, Shyam S., Lignani, Gabriele, Jepson, James E. C., Broda, Paolo, Baldassari, Simona, Rossi, Pia, Fruscione, Floriana, Madia, Francesca, Traverso, Monica, De-Marco, Patrizia, Pérez-Dueñas, Belen, Munell, Francina, Kriouile, Yamna, El-Khorassani, Mohamed, Karashova, Blagovesta, Avdjieva, Daniela, Kathom, Hadil, Tincheva, Radka, Van-Maldergem, Lionel, Nachbauer, Wolfgang, Boesch, Sylvia, Gagliano, Antonella, Amadori, Elisabetta, Goraya, Jatinder S., Sultan, Tipu, Kirmani, Salman, Ibrahim, Shahnaz, Jan, Farida, Mine, Jun, Banu, Selina, Veggiotti, Pierangelo, Zuccotti, Gian V., Ferrari, Michel D., Van Den Maagdenberg, Arn M. J., Verrotti, Alberto, Marseglia, Gian L., Savasta, Salvatore, Soler, Miguel A., Scuderi, Carmela, Borgione, Eugenia, Chimenz, Roberto, Gitto, Eloisa, Dipasquale, Valeria, Sallemi, Alessia, Fusco, Monica, Cuppari, Caterina, Cutrupi, Maria C., Ruggieri, Martino, Cama, Armando, Capra, Valeria, Mencacci, Niccolò E., Boles, Richard, Gupta, Neerja, Kabra, Madhulika, Papacostas, Savva, Zamba-Papanicolaou, Eleni, Dardiotis, Efthymio, Maqbool, Shazia, Rana, Nuzhat, Atawneh, Osama, Lim, Shen Y., Shaikh, Farooq, Koutsis, George, Breza, Marianthi, Coviello, Domenico A., Dauvilliers, Yves A., Alkhawaja, Issam, Alkhawaja, Mariam, Al-Mutairi, Fuad, Stojkovic, Tanya, Ferrucci, Veronica, Zollo, Massimo, Alkuraya, Fowzan S., Kinali, Maria, Sherifa, Hamed, Benrhouma, Hanene, Turki, Ilhem B. Y., Tazir, Meriem, Obeid, Makram, Bakhtadze, Sophia, Saadi, Nebal W., Zaki, Maha S., Triki, Chahnez C., Benfenati, Fabio, Gustincich, Stefano, Kara, Majdi, Belcastro, Vincenzo, Specchio, Nicola, Capovilla, Giuseppe, Karimiani, Ehsan G., Salih, Ahmed M., Okubadejo, Njideka U., Ojo, Oluwadamilola O., Oshinaike, Olajumoke O., Oguntunde, Olapeju, Wahab, Kolawole, Bello, Abiodun H., Abubakar, Sanni, Obiabo, Yahaya, Nwazor, Ernest, Ekenze, Oluchi, Williams, Uduak, Iyagba, Alagoma, Taiwo, Lolade, Komolafe, Morenikeji, Senkevich, Konstantin, Shashkin, Chingiz, Zharkynbekova, Nazira, Koneyev, Kairgali, Manizha, Ganieva, Isrofilov, Maksud, Guliyeva, Ulviyya, Salayev, Kamran, Khachatryan, Samson, Rossi, Salvatore, Silvestri, Gabriella, Haridy, Nourelhoda, Ramenghi, Luca A., Xiromerisiou, Georgia, David, Emanuele, Aguennouz, Mhammed, Fidani, Liana, Spanaki &amp, Cleanthe, Tucci, Arianna, Miquel, Raspall-Chaure, Michael, Chez, Anne, Tsai, Emily, Fassi, Marwan, Shinawi, John N, Constantino, Rita, De Zorzi, Sara, Fortuna, Fernando, Kok, Boris, Keren, Dominique, Bonneau, Murim, Choi, Bruria, Benzeev, Federico, Zara, Heather C, Mefford, Ingrid E, Scheffer, Jill, Clayton-Smith, Alfons, Macaya, James E, Rothman, Evan E, Eichler, Dimitri M, Kullmann, Henry, Houlden, Salvatore Rossi, and Gabriella Silvestri (ORCID:0000-0002-1950-1468)

Abstract

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission.

Published
2019

10. LRP10 in α-synucleinopathies

Author

Lasse Pihlstrøm, Lucia Schottlaender, Viorica Chelban, Henry Houlden, Safa Al-Sarraj, Thomas Arzberger, Conceicao Bettencourt, Kailash Bhatia, Dennis W Dickson, Monica Federoff, Ellen Gelpi, Steve Gentleman, John Hardy, Janice Holton, Inge Huitinga, Allan Levey, David Mann, Wassilios Meissner, Huw Morris, Chris Morris, Alan Pittman, Olivier Rascol, Peter Riederer, Ekaterina Rogaeva, Owen Ross, Sonja Scholtz, Andrew B Singleton, John Trojanowski, Jana Vandrovcova, Tom Warner, and Nick Wood

Subjects
Neurology (clinical)
Published
2018
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11. Genes that affect synaptic excitability and transmission identified by rare variant analyses in episodic ataxias

Author

Stephanie Efthymiou (1), Vincenzo Salpietro (1), Marisol Sampedro-Castañeda (1), Andreea Manole (1), Thomas Bourinaris (1, Emer O'Connor (1), Liana Veneziano (3), Elide Mantuano (3), Marina Frontali (3), Paola Giunti (1), Richard Boles (4, 5, Elena Dominguez Garrido (7), Conceicao Bettencourt (1), Juan A. Botia (1), Mina Ryten (1), Jana Vandrovcova (1), Samuel McCall (8), Robyn W. Labrum (8), Sameer Zuberi (9), Alfons Macaya (10), Dimitri M. Kullmann (11), Roope Manniko (1), Henry Houlden (1), Michael G. Hanna (1, 12), and SYNAPS Study Group

Subjects
Episodic ataxia, Synaptopathies, Transportopathies, Channelopathies, Paroxysmal neurological disorders
Abstract

The episodic ataxias are a heterogeneous group of paroxysmal neurological disorders characterized by intermittent attacks of unsteadiness and incoordination, often associated with additional neurological features including migraine or hemiplegic migraine, epilepsy, fluctuating weakness, or progressive ataxia. There are at least ten causative genes reported, with some of these only identified in isolated cases or families. Although separate screening studies have been carried out on each of the episodic ataxia genes, so far there has been no report of large study using a next generation sequencing approach in the analysis of these disorders, thus little is known about their molecular heterogeneity. The identification in the present study of rare variants in genes implicated in synaptic excitability and transmission highlight overlapping molecular pathways and pleiotropic clinical presentations in paroxysmal neurological disorders.

Published
2017

12. Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2

Author

Ellen, Cottenie, Andrzej, Kochanski, Albena, Jordanova, Boglarka, Bansagi, Magdalena, Zimon, Alejandro, Horga, Zane, Jaunmuktane, Paola, Saveri, Vedrana Milic, Rasic, Jonathan, Baets, Marina, Bartsakoulia, Rafal, Ploski, Pawel, Teterycz, Milos, Nikolic, Ros, Quinlivan, Matilde, Laura, Mary G, Sweeney, Franco, Taroni, Michael P, Lunn, Isabella, Moroni, Michael, Gonzalez, Michael G, Hanna, Conceicao, Bettencourt, Elodie, Chabrol, Andre, Franke, Katja, von Au, Markus, Schilhabel, Dagmara, Kabzińska, Irena, Hausmanowa-Petrusewicz, Sebastian, Brandner, Siew Choo, Lim, Haiwei, Song, Byung-Ok, Choi, Rita, Horvath, Ki-Wha, Chung, Stephan, Zuchner, Davide, Pareyson, Matthew, Harms, Mary M, Reilly, and Henry, Houlden

Subjects
Adult, Models, Molecular, Base Sequence, Molecular Sequence Data, Mutation, Missense, Chromosome Mapping, Sequence Analysis, DNA, Pedigree, Phenotype, Haplotypes, Sural Nerve, Charcot-Marie-Tooth Disease, Report, Protein Interaction Mapping, Humans, Exome, Female
Abstract

Using a combination of exome sequencing and linkage analysis, we investigated an English family with two affected siblings in their 40s with recessive Charcot-Marie Tooth disease type 2 (CMT2). Compound heterozygous mutations in the immunoglobulin-helicase-μ-binding protein 2 (IGHMBP2) gene were identified. Further sequencing revealed a total of 11 CMT2 families with recessively inherited IGHMBP2 gene mutations. IGHMBP2 mutations usually lead to spinal muscular atrophy with respiratory distress type 1 (SMARD1), where most infants die before 1 year of age. The individuals with CMT2 described here, have slowly progressive weakness, wasting and sensory loss, with an axonal neuropathy typical of CMT2, but no significant respiratory compromise. Segregating IGHMBP2 mutations in CMT2 were mainly loss-of-function nonsense in the 5′ region of the gene in combination with a truncating frameshift, missense, or homozygous frameshift mutations in the last exon. Mutations in CMT2 were predicted to be less aggressive as compared to those in SMARD1, and fibroblast and lymphoblast studies indicate that the IGHMBP2 protein levels are significantly higher in CMT2 than SMARD1, but lower than controls, suggesting that the clinical phenotype differences are related to the IGHMBP2 protein levels.

Published
2014

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