Mutations in KIF7 link Joubert syndrome with Sonic Hedgehog signaling and microtubule dynamics

J Clin Invest. 2011 Jul;121(7):2662-7. doi: 10.1172/JCI43639.


Joubert syndrome (JBTS) is characterized by a specific brain malformation with various additional pathologies. It results from mutations in any one of at least 10 different genes, including NPHP1, which encodes nephrocystin-1. JBTS has been linked to dysfunction of primary cilia, since the gene products known to be associated with the disorder localize to this evolutionarily ancient organelle. Here we report the identification of a disease locus, JBTS12, with mutations in the KIF7 gene, an ortholog of the Drosophila kinesin Costal2, in a consanguineous JBTS family and subsequently in other JBTS patients. Interestingly, KIF7 is a known regulator of Hedgehog signaling and a putative ciliary motor protein. We found that KIF7 co-precipitated with nephrocystin-1. Further, knockdown of KIF7 expression in cell lines caused defects in cilia formation and induced abnormal centrosomal duplication and fragmentation of the Golgi network. These cellular phenotypes likely resulted from abnormal tubulin acetylation and microtubular dynamics. Thus, we suggest that modified microtubule stability and growth direction caused by loss of KIF7 function may be an underlying disease mechanism contributing to JBTS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple
  • Animals
  • Cerebellar Diseases / genetics*
  • Cerebellar Diseases / physiopathology
  • Cerebellum / abnormalities
  • Chromosomes, Human, Pair 15
  • Consanguinity
  • DNA Mutational Analysis
  • Drosophila / genetics
  • Drosophila / metabolism
  • Eye Abnormalities / genetics*
  • Eye Abnormalities / physiopathology
  • Golgi Apparatus / pathology
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism*
  • Humans
  • Kidney Diseases, Cystic / genetics*
  • Kidney Diseases, Cystic / physiopathology
  • Kinesins / genetics*
  • Kinesins / metabolism
  • Male
  • Mice
  • Microtubules / metabolism*
  • Pedigree
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Retina / abnormalities
  • Retina / physiopathology
  • Signal Transduction / physiology*
  • Tissue Distribution


  • Hedgehog Proteins
  • KIF7 protein, human
  • RNA, Small Interfering
  • SHH protein, human
  • Kinesins

Supplementary concepts

  • Agenesis of Cerebellar Vermis