Complex interactions between genes controlling trafficking in primary cilia

Nat Genet. 2011 Jun;43(6):547-53. doi: 10.1038/ng.832. Epub 2011 May 8.

Abstract

Cilia-associated human genetic disorders are striking in the diversity of their abnormalities and their complex inheritance. Inactivation of the retrograde ciliary motor by mutations in DYNC2H1 causes skeletal dysplasias that have strongly variable expressivity. Here we define previously unknown genetic relationships between Dync2h1 and other genes required for ciliary trafficking. Mutations in mouse Dync2h1 disrupt cilia structure, block Sonic hedgehog signaling and cause midgestation lethality. Heterozygosity for Ift172, a gene required for anterograde ciliary trafficking, suppresses cilia phenotypes, Sonic hedgehog signaling defects and early lethality of Dync2h1 homozygotes. Ift122, like Dync2h1, is required for retrograde ciliary trafficking, but reduction of Ift122 gene dosage also suppresses the Dync2h1 phenotype. These genetic interactions illustrate the cell biology underlying ciliopathies and argue that mutations in intraflagellar transport genes cause their phenotypes because of their roles in cilia architecture rather than direct roles in signaling.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Carrier Proteins / metabolism
  • Cilia / genetics*
  • Cytoplasmic Dyneins / genetics*
  • Cytoskeletal Proteins
  • Fibroblasts / metabolism
  • Hedgehog Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / physiology
  • Mice
  • Mutation

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Cytoskeletal Proteins
  • DYNC2H1 protein, human
  • Hedgehog Proteins
  • Ift122 protein, mouse
  • Ift172 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Shh protein, mouse
  • Cytoplasmic Dyneins