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PLoS Genet. 2017 Aug 31;13(8):e1006957. doi: 10.1371/journal.pgen.1006957. eCollection 2017 Aug.

MYT1L mutations cause intellectual disability and variable obesity by dysregulating gene expression and development of the neuroendocrine hypothalamus.

Author information

1
Département de Génétique Médicale, Hôpital Arnaud de Villeneuve, Montpellier Cedex 5, France.
2
Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, United States of America.
3
Service de génétique médicale, Hôpitaux Universitaires de Clermont-Ferrand, Clermont-Ferrand, France.
4
Human Genetics and Genomics, HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, United States of America.
5
Centre de génétique chromosomique, 51 Boulevard de Belfort, Lille, France.
6
Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
7
Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France.
8
Service de neuropédiatrie, Hôpital Saint Vincent de Paul, Lille, France.
9
South East Thames Regional Genetics Service, Guy's Hospital, London, United Kingdom.
10
North West Thames Regional Genetics Centre, Northwick Park Hospital, Harrow, United Kingdom.
11
Clinical Genetics Unit, Birmingham Women's Hospital, Birmingham, United Kingdom.
12
Peninsula Clinical Genetics, Royal Devon & Exeter Hospital (Heavitree), Exeter, United Kingdom.
13
Department of Molecular Biology and Biotechnology, The University of Sheffield, Sheffield, United Kingdom.
14
Department of Medical Genetics, CHU Hautepierre, Strasbourg, France.
15
Department of Medicine, Georgetown University, Washington, DC, United States of America.
16
Sheffield Institute for Translational Neuroscience, The University of Sheffield, Sheffield, United Kingdom.
17
Sheffield Clinical Genetics Service, Sheffield Children's Hospital NHS Foundation Trust, Sheffield, United Kingdom.

Abstract

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.

PMID:
28859103
PMCID:
PMC5597252
DOI:
10.1371/journal.pgen.1006957
[Indexed for MEDLINE]
Free PMC Article

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