Mutations in the gene encoding IFT dynein complex component WDR34 cause Jeune asphyxiating thoracic dystrophy

Am J Hum Genet. 2013 Nov 7;93(5):932-44. doi: 10.1016/j.ajhg.2013.10.003. Epub 2013 Oct 31.

Abstract

Bidirectional (anterograde and retrograde) motor-based intraflagellar transport (IFT) governs cargo transport and delivery processes that are essential for primary cilia growth and maintenance and for hedgehog signaling functions. The IFT dynein-2 motor complex that regulates ciliary retrograde protein transport contains a heavy chain dynein ATPase/motor subunit, DYNC2H1, along with other less well functionally defined subunits. Deficiency of IFT proteins, including DYNC2H1, underlies a spectrum of skeletal ciliopathies. Here, by using exome sequencing and a targeted next-generation sequencing panel, we identified a total of 11 mutations in WDR34 in 9 families with the clinical diagnosis of Jeune syndrome (asphyxiating thoracic dystrophy). WDR34 encodes a WD40 repeat-containing protein orthologous to Chlamydomonas FAP133, a dynein intermediate chain associated with the retrograde intraflagellar transport motor. Three-dimensional protein modeling suggests that the identified mutations all affect residues critical for WDR34 protein-protein interactions. We find that WDR34 concentrates around the centrioles and basal bodies in mammalian cells, also showing axonemal staining. WDR34 coimmunoprecipitates with the dynein-1 light chain DYNLL1 in vitro, and mining of proteomics data suggests that WDR34 could represent a previously unrecognized link between the cytoplasmic dynein-1 and IFT dynein-2 motors. Together, these data show that WDR34 is critical for ciliary functions essential to normal development and survival, most probably as a previously unrecognized component of the mammalian dynein-IFT machinery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asian Continental Ancestry Group / genetics
  • Axoneme / genetics
  • Carrier Proteins / genetics*
  • Child
  • Chlamydomonas / genetics
  • Cilia / genetics
  • Cilia / metabolism
  • Cytoplasmic Dyneins / genetics*
  • Cytoskeleton / genetics
  • Cytoskeleton / metabolism
  • Ellis-Van Creveld Syndrome / genetics*
  • Ellis-Van Creveld Syndrome / pathology
  • European Continental Ancestry Group / genetics
  • Exome
  • Exons
  • Humans
  • Infant
  • Infant, Newborn
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Mutation
  • Protein Conformation
  • Proteomics

Substances

  • Carrier Proteins
  • DYNC1H1 protein, human
  • DYNC2H1 protein, human
  • Intracellular Signaling Peptides and Proteins
  • WDR34 protein, human
  • DYNLL1 protein, human
  • Cytoplasmic Dyneins

Supplementary concepts

  • Jeune syndrome