دورية أكاديمية
MYT1L mutations cause intellectual disability and variable obesity by dysregulating gene expression and development of the neuroendocrine hypothalamus.
| العنوان: | MYT1L mutations cause intellectual disability and variable obesity by dysregulating gene expression and development of the neuroendocrine hypothalamus. |
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| المؤلفون: | Blanchet, P., Bebin, M., Bruet, S., Cooper, G. M., Thompson, M. L., Duban-Bedu, B., Gerard, B., Piton, A., Suckno, S., Deshpande, C., Clowes, V., Vogt, J., Turnpenny, Peter, Williamson, M. P., Alembik, Y., Glasgow, E., McNeill, A. |
| بيانات النشر: | PLoS |
| سنة النشر: | 2017 |
| المجموعة: | RD&E Research Repository (Royal Devon and Exeter NHS Foundation Trust) |
| مصطلحات موضوعية: | Wessex Classification Subject Headings::Oncology. Pathology.::Genetics, Adult, Animals, CRISPR-Cas Systems, Cell Line, Child, Chromosome Deletion, Chromosomes, Human, Pair 2, Female, Gene Expression Regulation, Gene Knockout Techniques, Humans, Hypothalamus, Intellectual Disability, Male, Mutation, Nerve Tissue Proteins, Obesity, Polymorphism, Single Nucleotide, Transcription Factors, Zebrafish |
| الوصف: | Deletions at chromosome 2p25.3 are associated with a syndrome consisting of intellectual disability and obesity. The smallest region of overlap for deletions at 2p25.3 contains PXDN and MYT1L. MYT1L is expressed only within the brain in humans. We hypothesized that single nucleotide variants (SNVs) in MYT1L would cause a phenotype resembling deletion at 2p25.3. To examine this we sought MYT1L SNVs in exome sequencing data from 4, 296 parent-child trios. Further variants were identified through a genematcher-facilitated collaboration. We report 9 patients with MYT1L SNVs (4 loss of function and 5 missense). The phenotype of SNV carriers overlapped with that of 2p25.3 deletion carriers. To identify the transcriptomic consequences of MYT1L loss of function we used CRISPR-Cas9 to create a knockout cell line. Gene Ontology analysis in knockout cells demonstrated altered expression of genes that regulate gene expression and that are localized to the nucleus. These differentially expressed genes were enriched for OMIM disease ontology terms "mental retardation". To study the developmental effects of MYT1L loss of function we created a zebrafish knockdown using morpholinos. Knockdown zebrafish manifested loss of oxytocin expression in the preoptic neuroendocrine area. This study demonstrates that MYT1L variants are associated with syndromic obesity in humans. The mechanism is related to dysregulated expression of neurodevelopmental genes and altered development of the neuroendocrine hypothalamus. ; This article is freely available online via Open Access. Click on the Additional Link above to access the full-text via the publisher's site. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1553-7404 28859103 |
| العلاقة: | http://dx.plos.org/10.1371/journal.pgen.1006957Test; MYT1L mutations cause intellectual disability and variable obesity by dysregulating gene expression and development of the neuroendocrine hypothalamus. 2017, 13 (8):e1006957 PLoS Genet.; http://hdl.handle.net/11287/620470Test; PLoS genetics |
| DOI: | 10.1371/journal.pgen.1006957 |
| الإتاحة: | https://doi.org/10.1371/journal.pgen.1006957Test http://hdl.handle.net/11287/620470Test |
| حقوق: | Archived with thanks to PLoS genetics. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
| رقم الانضمام: | edsbas.4B39225B |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 15537404 28859103 |
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| DOI: | 10.1371/journal.pgen.1006957 |