Mutations in KIAA0586 Cause Lethal Ciliopathies Ranging from a Hydrolethalus Phenotype to Short-Rib Polydactyly Syndrome

Am J Hum Genet. 2015 Aug 6;97(2):311-8. doi: 10.1016/j.ajhg.2015.06.003. Epub 2015 Jul 9.

Abstract

KIAA0586, the human ortholog of chicken TALPID3, is a centrosomal protein that is essential for primary ciliogenesis. Its disruption in animal models causes defects attributed to abnormal hedgehog signaling; these defects include polydactyly and abnormal dorsoventral patterning of the neural tube. Here, we report homozygous mutations of KIAA0586 in four families affected by lethal ciliopathies ranging from a hydrolethalus phenotype to short-rib polydactyly. We show defective ciliogenesis, as well as abnormal response to SHH-signaling activation in cells derived from affected individuals, consistent with a role of KIAA0586 in primary cilia biogenesis. Whereas centriolar maturation seemed unaffected in mutant cells, we observed an abnormal extended pattern of CEP290, a centriolar satellite protein previously associated with ciliopathies. Our data show the crucial role of KIAA0586 in human primary ciliogenesis and subsequent abnormal hedgehog signaling through abnormal GLI3 processing. Our results thus establish that KIAA0586 mutations cause lethal ciliopathies.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Cell Cycle Proteins / genetics*
  • Ciliary Motility Disorders / genetics*
  • Ciliary Motility Disorders / pathology
  • Codon, Nonsense / genetics*
  • Europe, Eastern
  • Fatal Outcome
  • Founder Effect
  • Hand Deformities, Congenital / genetics*
  • Heart Defects, Congenital / genetics*
  • Humans
  • Hydrocephalus / genetics*
  • Likelihood Functions
  • Molecular Sequence Data
  • Pedigree
  • Phenotype*
  • Sequence Analysis, DNA
  • Short Rib-Polydactyly Syndrome / genetics*

Substances

  • Cell Cycle Proteins
  • Codon, Nonsense
  • Talpid3 protein, human

Supplementary concepts

  • Hydrolethalus syndrome