ZFIN ID: ZDB-PUB-121205-15
Recurrent De Novo Mutations in PACS1 Cause Defective Cranial-Neural-Crest Migration and Define a Recognizable Intellectual-Disability Syndrome
Schuurs-Hoeijmakers, J.H., Oh, E.C., Vissers, L.E., Swinkels, M.E., Gilissen, C., Willemsen, M.A., Holvoet, M., Steehouwer, M., Veltman, J.A., de Vries, B.B., van Bokhoven, H., de Brouwer, A.P., Katsanis, N., Devriendt, K., and Brunner, H.G.
Date: 2012
Source: American journal of human genetics   91(6): 1122-1127 (Journal)
Registered Authors: Katsanis, Nicholas
Keywords: none
MeSH Terms:
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Facies
  • Humans
  • Intellectual Disability/diagnosis
  • Intellectual Disability/genetics*
  • Male
  • Mutation*
  • Neural Crest/embryology
  • Neural Crest/metabolism*
  • Syndrome
  • Vesicular Transport Proteins/genetics*
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/metabolism
PubMed: 23159249 Full text @ Am. J. Hum. Genet.

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.