ZFIN ID: ZDB-PUB-180426-12
Novel CASK mutations in cases with syndromic microcephaly
Cristofoli, F., Devriendt, K., Davis, E.E., Van Esch, H., Vermeesch, J.R.
Date: 2018
Source: Human Mutation   39(7): 993-1001 (Journal)
Registered Authors: Davis, Erica
Keywords: CASK, cerebellar defects, loss-of-function, microcephaly, zebrafish
MeSH Terms:
  • Animals
  • Cerebellum/physiopathology
  • Female
  • Genes, X-Linked/genetics
  • Genetic Predisposition to Disease*
  • Guanylate Kinases/genetics*
  • Humans
  • Intellectual Disability/genetics*
  • Intellectual Disability/physiopathology
  • Loss of Function Mutation/genetics
  • Male
  • Microcephaly/genetics*
  • Microcephaly/physiopathology
  • Mutation
  • Phenotype
  • Whole Exome Sequencing
  • Zebrafish/genetics
PubMed: 29691940 Full text @ Hum. Mutat.
Mutations in CASK cause a wide spectrum of phenotypes in humans ranging from mild X-linked intellectual disability to a severe microcephaly (MC) and pontocerebellar hypoplasia syndrome. Nevertheless, predicting pathogenicity and phenotypic consequences of novel CASK mutations through the exclusive consideration of genetic information and population-based data remains a challenge. Using whole exome sequencing, we identified four novel CASK mutations in individuals with syndromic MC. To understand the functional consequences of the different point mutations on the development of MC and cerebellar defects we established a transient loss of function zebrafish model, and demonstrate recapitulation of relevant neuroanatomical phenotypes. Furthermore, we utilized in vivo complementation studies to demonstrate that the three point mutations confer a loss of function effect. This work endorses zebrafish as a tractable model to rapidly assess the effect of novel CASK variants on brain development. This article is protected by copyright. All rights reserved.