Recurrent de novo mutations in PACS1 cause defective cranial-neural-crest migration and define a recognizable intellectual-disability syndrome.


Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Schuurs-Hoeijmakers, JHM; Oh, EC; Vissers, LELM; Swinkels, MEM; Gilissen, C; Willemsen, MA; Holvoet, M; Steehouwer, M; Veltman, JA; de Vries, BBA; van Bokhoven, H; de Brouwer, APM; Katsanis, N; Devriendt, K; Brunner, HG

Published Date

  • December 7, 2012

Published In

Volume / Issue

  • 91 / 6

Start / End Page

  • 1122 - 1127

PubMed ID

  • 23159249

Pubmed Central ID

  • 23159249

Electronic International Standard Serial Number (EISSN)

  • 1537-6605

Digital Object Identifier (DOI)

  • 10.1016/j.ajhg.2012.10.013


  • eng

Conference Location

  • United States