Department of Human Genetics 855, Nijmegen Centre for Molecular Life Sciences and Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
Am J Hum Genet. 2012 Dec 7;91(6):1122-7. doi: 10.1016/j.ajhg.2012.10.013. Epub 2012 Nov 15.
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 PACS1 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.
我们研究了两个具有智力障碍（ID）和显著面部相似性的非相关男孩，这表明存在一种迄今尚未被认识到的综合征。在两个家庭的外显子组测序中均发现了 PACS1 中的相同新生突变，提示其因果关系。为了支持这些遗传发现并了解突变的发病机制，我们进行了体外和体内研究。改变的 PACS1 形式在体外形成细胞质聚集体，同时增加了蛋白质稳定性，并显示与 TRPV4 的同工型特异性变体结合受损，但与全长蛋白结合不受影响。此外，与人类病理学一致，突变型 PACS1 mRNA 在斑马鱼胚胎中的表达最可能以显性负性方式诱导颅面缺陷。这种表型是由 SOX10 阳性颅神经嵴细胞而不是肠神经嵴细胞的异常特化和迁移驱动的。我们的研究结果表明 PACS1 对于颅面结构的形成是必要的，并且其功能的扰动导致特定的综合征性 ID 表型。
