MYT1L mutations cause intellectual disability and variable obesity by dysregulating gene expression and development of the neuroendocrine hypothalamus.
MYT1L mutations cause intellectual disability and variable obesity by dysregulating gene expression and development of the neuroendocrine hypothalamus.
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DOI：
10.1371/journal.pgen.1006957
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发表时间：
2017-08
期刊：
影响因子：
4.5
通讯作者：
McNeill A
中科院分区：
文献类型：
--
作者：
Blanchet P;Bebin M;Bruet S;Cooper GM;Thompson ML;Duban-Bedu B;Gerard B;Piton A;Suckno S;Deshpande C;Clowes V;Vogt J;Turnpenny P;Williamson MP;Alembik Y;Clinical Sequencing Exploratory Research Study Consortium;Deciphering Developmental Disorders Consortium;Glasgow E;McNeill A
染色体2p25.3缺失与智力残疾和肥胖等综合征有关。2p25.3缺失的最小重叠区域包含PXDN和MYT1L。MYT1L仅在人类大脑中表达。我们假设MYT1L的单核苷酸变异（snv）会导致类似于2p25.3缺失的表型。为了验证这一点，我们在4296对亲子三胞胎的外显子组测序数据中寻找MYT1L snv。进一步的变异是通过基因匹配者促进的合作确定的。我们报告了9例MYT1L snv患者（4例功能丧失，5例义错）。SNV携带者的表型与2p25.3缺失携带者的表型重叠。为了确定MYT1L功能丧失的转录组学后果，我们使用CRISPR-Cas9创建了一个敲除细胞系。基因本体论分析在敲除细胞显示基因的表达改变，调节基因表达和定位于细胞核。这些差异表达的基因在OMIM疾病本体术语“智力低下”中被富集。为了研究MYT1L功能丧失对发育的影响，我们利用morpholinos构建了一个斑马鱼基因敲低。抑制斑马鱼在视前神经内分泌区表现出催产素表达缺失。这项研究表明，MYT1L变异与人类综合征性肥胖有关。其机制与神经发育基因表达失调和下丘脑神经内分泌发育改变有关。智力残疾的定义是智商低于70分，每100人中约有2-3人患有这种疾病。肥胖被定义为成人体重指数超过30或儿童体重指数超过95百分位。这两种情况都是西方国家主要的公共卫生问题。遗传学研究表明，染色体的小片段缺失（缺失，会移除许多基因）和基因字母的改变（会阻止基因的工作，突变）会导致智力残疾或肥胖。在这里，我们确定了9名患有智力残疾和肥胖的儿童，他们的MYT1L基因发生了突变。这种基因被认为对大脑发育有重要的指导作用。为了找出MYT1L缺失对大脑发育的影响，我们（使用一种特殊的化学物质）降低了实验性斑马鱼的MYT1L水平。这表明，斑马鱼MYT1L的缺失会导致下丘脑发育出现问题，这可能解释了MYT1L突变是如何导致人类肥胖的。在斑马鱼身上，一种叫做催产素的大脑激素也减少了，这种激素与思维过程有关，这可以解释为什么MYT1L突变会导致智力残疾。我们已经确定了由MYT1L突变引起的一种新的遗传状况，对该基因的进一步研究将有助于我们理解和治疗智力残疾和肥胖。
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. Intellectual disability is defined by having an intelligence quotient of less than 70 points, and it affects about 2–3 people in every 100. Obesity is defined as having a body mass index of over 30 in adults or over the 95th centile in children. Both of these conditions are major public health concerns in Western countries. Genetic studies have shown that small missing pieces of chromosome (deletions, which remove many genes) and changes to the lettering of genes (which stop the gene from working, mutations) can cause intellectual disability or obesity. Here we identified 9 children with intellectual disability and obesity who have mutations in a gene called MYT1L. This gene is thought to give an important instruction for brain development. To find out what the effect of loss of MYT1L is on brain development we reduced the levels of MYT1L (using a special chemical) in an experimental zebrafish. This showed that loss of MYT1L in zebrafish causes a problem with the development of the hypothalamus, which may explain how MYT1L mutations cause obesity in humans. In the zebrafish there was also reduction of a brain hormone called oxytocin which is involved in thought processes, which may explain why MYT1L mutations cause intellectual disability. We have identified a new genetic condition caused by MYT1L mutations, further study of this gene will help us understand, and treat, intellectual disability and obesity.
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影响因子：
14.9
作者：
Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
通讯作者：
Ma'ayan A
DOI：
10.1038/nrg3413
发表时间：
2013-05
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
9.8
作者：
Kasher, Paul R.;Schertz, Katherine E.;Banka, Siddharth
通讯作者：
Banka, Siddharth
影响因子：
9.8
作者：
Khan, Kamron;Rudkin, Adam;Ali, Manir
通讯作者：
Ali, Manir
影响因子：
8.8
作者：
De Rocker, Nina;Vergult, Sarah;Menten, Bjoern
通讯作者：
Menten, Bjoern