KIF7 Mutations Cause Fetal Hydrolethalus and Acrocallosal Syndromes

Nat Genet. 2011 Jun;43(6):601-6. doi: 10.1038/ng.826. Epub 2011 May 8.

Abstract

KIF7, the human ortholog of Drosophila Costal2, is a key component of the Hedgehog signaling pathway. Here we report mutations in KIF7 in individuals with hydrolethalus and acrocallosal syndromes, two multiple malformation disorders with overlapping features that include polydactyly, brain abnormalities and cleft palate. Consistent with a role of KIF7 in Hedgehog signaling, we show deregulation of most GLI transcription factor targets and impaired GLI3 processing in tissues from individuals with KIF7 mutations. KIF7 is also a likely contributor of alleles across the ciliopathy spectrum, as sequencing of a diverse cohort identified several missense mutations detrimental to protein function. In addition, in vivo genetic interaction studies indicated that knockdown of KIF7 could exacerbate the phenotype induced by knockdown of other ciliopathy transcripts. Our data show the role of KIF7 in human primary cilia, especially in the Hedgehog pathway through the regulation of GLI targets, and expand the clinical spectrum of ciliopathies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrocallosal Syndrome / genetics*
  • Acrocallosal Syndrome / pathology
  • Adolescent
  • Cerebral Ventricles / pathology
  • Child
  • Child, Preschool
  • Cilia / genetics
  • Consanguinity
  • Female
  • Hand Deformities, Congenital / embryology
  • Hand Deformities, Congenital / genetics
  • Hand Deformities, Congenital / pathology
  • Heart Defects, Congenital / embryology
  • Heart Defects, Congenital / genetics
  • Heart Defects, Congenital / pathology
  • Hedgehog Proteins / metabolism
  • Humans
  • Hydrocephalus / embryology
  • Hydrocephalus / genetics
  • Hydrocephalus / pathology
  • Infant
  • Kinesin / genetics*
  • Magnetic Resonance Imaging
  • Male
  • Mutation
  • Pedigree

Substances

  • Hedgehog Proteins
  • KIF7 protein, human
  • Kinesin

Supplementary concepts

  • Hydrolethalus syndrome

Associated data

  • RefSeq/NM_198525