دورية أكاديمية
Recessive PRDM13 mutations cause fatal perinatal brainstem dysfunction with cerebellar hypoplasia and disrupt Purkinje cell differentiation
| العنوان: | Recessive PRDM13 mutations cause fatal perinatal brainstem dysfunction with cerebellar hypoplasia and disrupt Purkinje cell differentiation |
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| المؤلفون: | Coolen, M., Altin, N., Rajamani, K., Pereira, E., Siquier-Pernet, K., Puig Lombardi, E., Moreno, N., Barcia, G., Yvert, M., Laquerrière, A., Pouliet, A., Nitschké, P., Boddaert, N., Rausell, A., Razavi, F., Afenjar, A., Billette de Villemeur, T., Al-Maawali, A., Al-Thihli, K., Baptista, J., Beleza-Meireles, A., Garel, C., Legendre, M., Gelot, A., Burglen, L., Moutton, S., Cantagrel, V. |
| بيانات النشر: | Cell Press |
| سنة النشر: | 2022 |
| المجموعة: | RD&E Research Repository (Royal Devon and Exeter NHS Foundation Trust) |
| مصطلحات موضوعية: | Animals, Brain Diseases/pathology, Brain Stem, Cerebellum/abnormalities/pathology, Developmental Disabilities, Histone-Lysine N-Methyltransferase/genetics, Humans, Mice, Mutation/genetics, Nervous System Malformations, Neurogenesis/genetics, Purkinje Cells/metabolism, Transcription Factors/genetics, Zebrafish/metabolism, Prdm13, Purkinje cells, brainstem, cerebellum, inferior olive nuclei, neurodevelopment, neuronal specification, olivopontocerebellar hypoplasia, zebrafish |
| الوصف: | Pontocerebellar hypoplasias (PCHs) are congenital disorders characterized by hypoplasia or early atrophy of the cerebellum and brainstem, leading to a very limited motor and cognitive development. Although over 20 genes have been shown to be mutated in PCHs, a large proportion of affected individuals remains undiagnosed. We describe four families with children presenting with severe neonatal brainstem dysfunction and pronounced deficits in cognitive and motor development associated with four different bi-allelic mutations in PRDM13, including homozygous truncating variants in the most severely affected individuals. Brain MRI and fetopathological examination revealed a PCH-like phenotype, associated with major hypoplasia of inferior olive nuclei and dysplasia of the dentate nucleus. Notably, histopathological examinations highlighted a sparse and disorganized Purkinje cell layer in the cerebellum. PRDM13 encodes a transcriptional repressor known to be critical for neuronal subtypes specification in the mouse retina and spinal cord but had not been implicated, so far, in hindbrain development. snRNA-seq data mining and in situ hybridization in humans show that PRDM13 is expressed at early stages in the progenitors of the cerebellar ventricular zone, which gives rise to cerebellar GABAergic neurons, including Purkinje cells. We also show that loss of function of prdm13 in zebrafish leads to a reduction in Purkinje cells numbers and a complete absence of the inferior olive nuclei. Altogether our data identified bi-allelic mutations in PRDM13 as causing a olivopontocerebellar hypoplasia syndrome and suggest that early deregulations of the transcriptional control of neuronal fate specification could contribute to a significant number of cases. ; The article is available via Open Access. Click on the 'Additional link' above to access the full-text. ; Published version, accepted version (6 month embargo), submitted version |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | https://linkinghub.elsevier.com/retrieve/pii/S0002-9297Test(22)00106-9; Am J Hum Genet. 2022 May 5;109(5):909-927. doi:10.1016/j.ajhg.2022.03.010. Epub 2022 Apr 6.; https://rde.dspace-express.com/handle/11287/622634Test; American journal of human genetics; PMC9118116 |
| DOI: | 10.1016/j.ajhg.2022.03.010 |
| الإتاحة: | https://doi.org/10.1016/j.ajhg.2022.03.010Test https://rde.dspace-express.com/handle/11287/622634Test |
| حقوق: | Copyright © 2022 American Society of Human Genetics. All rights reserved. ; http://creativecommons.org/publicdomain/zero/1.0Test/ |
| رقم الانضمام: | edsbas.81B53FA3 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1016/j.ajhg.2022.03.010 |
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