Recurrent De Novo Mutations in PACS1 Cause Defective Cranial-Neural-Crest Migration and Define a Recognizable Intellectual-Disability Syndrome
Recurrent De Novo Mutations in PACS1 Cause Defective Cranial-Neural-Crest Migration and Define a Recognizable Intellectual-Disability Syndrome
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DOI：
10.1016/j.ajhg.2012.10.013
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发表时间：
2012-12-07
影响因子：
9.8
通讯作者：
Brunner, Han G.
中科院分区：
文献类型：
--
作者：
Schuurs-Hoeijmakers, Janneke H. M.;Oh, Edwin C.;Brunner, Han G.
我们研究了两个没有血缘关系的男孩，他们都患有智力障碍，而且面部特征惊人地相似，这表明他们患有一种迄今为止尚未得到重视的综合征。两个家族的外显子组测序鉴定出相同的PACS1新生突变，提示因果关系。为了支持这些遗传发现并了解突变的病理机制，我们在体外和体内研究了蛋白质。改变的PACS1在体外形成细胞质聚集体，伴随着蛋白质稳定性的增加，并显示与TRPV4的同种型特异性变体的结合受损，但不与全长蛋白质结合。此外，与人类病理学一致，斑马鱼胚胎中突变PACS mRNA的表达最有可能以显性负性方式诱导颅面缺陷。这种表型是由SOX 10阳性颅神经嵴细胞的异常特异性和迁移驱动的，而不是肠神经嵴细胞。我们的研究结果表明，PACS1是必要的颅面结构的形成，其功能的扰动导致一个特定的综合征ID表型。
We studied two unrelated boys with intellectual disability (ID) and a striking facial resemblance suggestive of a hitherto unappreciated syndrome. Exome sequencing in both families identified identical de novo mutations in PACS1, suggestive of causality. To support these genetic findings and to understand the pathomechanism of the mutation, we studied the protein in vitro and in vivo. Altered PACS1 forms cytoplasmic aggregates in vitro with concomitant increased protein stability and shows impaired binding to an isoform-specific variant of TRPV4, but not the full-length protein. Furthermore, consistent with the human pathology, expression of mutant PACS, mRNA in zebrafish embryos induces craniofacial defects most likely in a dominant-negative fashion. This phenotype is driven by aberrant specification and migration of SOX10-positive cranial, but not enteric, neural-crest cells. Our findings suggest that PACS1 is necessary for the formation of craniofacial structures and that perturbation of its functions results in a specific syndromic ID phenotype.