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

2.50
Hdl Handle:
http://hdl.handle.net/11287/620470
Title:
MYT1L mutations cause intellectual disability and variable obesity by dysregulating gene expression and development of the neuroendocrine hypothalamus.
Authors:
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.
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.
Citation:
MYT1L mutations cause intellectual disability and variable obesity by dysregulating gene expression and development of the neuroendocrine hypothalamus. 2017, 13 (8):e1006957 PLoS Genet.
Publisher:
PLoS
Journal:
PLoS genetics
Issue Date:
Aug-2017
URI:
http://hdl.handle.net/11287/620470
DOI:
10.1371/journal.pgen.1006957
PubMed ID:
28859103
Additional Links:
http://dx.plos.org/10.1371/journal.pgen.1006957
Note:
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.
Type:
Journal Article
Language:
en
ISSN:
1553-7404
Appears in Collections:
Clinical Genetics (Peninsula Genetics); 2017 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorBlanchet, P.en
dc.contributor.authorBebin, M.en
dc.contributor.authorBruet, S.en
dc.contributor.authorCooper, G. M.en
dc.contributor.authorThompson, M. L.en
dc.contributor.authorDuban-Bedu, B.en
dc.contributor.authorGerard, B.en
dc.contributor.authorPiton, A.en
dc.contributor.authorSuckno, S.en
dc.contributor.authorDeshpande, C.en
dc.contributor.authorClowes, V.en
dc.contributor.authorVogt, J.en
dc.contributor.authorTurnpenny, Peteren
dc.contributor.authorWilliamson, M. P.en
dc.contributor.authorAlembik, Y.en
dc.contributor.authorGlasgow, E.en
dc.contributor.authorMcNeill, A.en
dc.date.accessioned2017-10-24T14:26:44Z-
dc.date.available2017-10-24T14:26:44Z-
dc.date.issued2017-08-
dc.identifier.citationMYT1L mutations cause intellectual disability and variable obesity by dysregulating gene expression and development of the neuroendocrine hypothalamus. 2017, 13 (8):e1006957 PLoS Genet.en
dc.identifier.issn1553-7404-
dc.identifier.pmid28859103-
dc.identifier.doi10.1371/journal.pgen.1006957-
dc.identifier.urihttp://hdl.handle.net/11287/620470-
dc.description.abstractDeletions 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.en
dc.language.isoenen
dc.publisherPLoSen
dc.relation.urlhttp://dx.plos.org/10.1371/journal.pgen.1006957en
dc.rightsArchived 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.en
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.subject.meshAdult-
dc.subject.meshAnimals-
dc.subject.meshCRISPR-Cas Systems-
dc.subject.meshCell Line-
dc.subject.meshChild-
dc.subject.meshChromosome Deletion-
dc.subject.meshChromosomes, Human, Pair 2-
dc.subject.meshFemale-
dc.subject.meshGene Expression Regulation-
dc.subject.meshGene Knockout Techniques-
dc.subject.meshHumans-
dc.subject.meshHypothalamus-
dc.subject.meshIntellectual Disability-
dc.subject.meshMale-
dc.subject.meshMutation-
dc.subject.meshNerve Tissue Proteins-
dc.subject.meshObesity-
dc.subject.meshPolymorphism, Single Nucleotide-
dc.subject.meshTranscription Factors-
dc.subject.meshZebrafish-
dc.titleMYT1L mutations cause intellectual disability and variable obesity by dysregulating gene expression and development of the neuroendocrine hypothalamus.en
dc.typeJournal Articleen
dc.identifier.journalPLoS geneticsen
dc.description.noteThis article is freely available online via Open Access. Click on the Additional Link above to access the full-text via the publisher's site.en
dc.type.versionPublisheden

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