2. Academic Validation
  3. IFT52 mutations destabilize anterograde complex assembly, disrupt ciliogenesis and result in short rib polydactyly syndrome

IFT52 mutations destabilize anterograde complex assembly, disrupt ciliogenesis and result in short rib polydactyly syndrome

  • Hum Mol Genet. 2016 Sep 15;25(18):4012-4020. doi: 10.1093/hmg/ddw241.
Wenjuan Zhang 1,  S Paige Taylor 2,  Lisette Nevarez 1,  Ralph S Lachman 3,  Deborah A Nickerson 4 5,  Michael Bamshad 4 5 6 7,  University of Washington Center for Mendelian Genomics Consortium,  Deborah Krakow 2 3 8 9,  Daniel H Cohn 10 3 9 1
Affiliations

Affiliations

  • 1 Department of Molecular, Cell, and Developmental Biology.
  • 2 Department of Human Genetics.
  • 3 International Skeletal Dysplasia Registry, University of California, Los Angeles, California, USA.
  • 4 Department of Genome Sciences.
  • 5 University of Washington Center for Mendelian Genomics.
  • 6 Department of Pediatrics, University of Washington, Seattle, Washington, USA.
  • 7 Division of Genetic Medicine, Seattle Children's Hospital, Seattle, Washington, USA.
  • 8 Department of Obstetrics and Gynecology.
  • 9 Department of Orthopaedic Surgery and Orthopaedic Hospital Research Center, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
  • 10 Department of Molecular, Cell, and Developmental Biology [email protected].
PMID: 27466190 DOI: 10.1093/hmg/ddw241
Abstract

The short-rib polydactyly syndromes (SRPS) encompass a radiographically and genetically heterogeneous group of skeletal ciliopathies that are characterized by a long narrow chest, short extremities, and variable occurrence of polydactyly. Radiographic abnormalities include undermineralization of the calvarium, shortened and bowed appendicular bones, trident shaped acetabula and polydactyly. In a case of SRPS we identified compound heterozygosity for mutations in IFT52, which encodes a component of the anterograde intraflagellar transport complex. The IFT52 mutant cells synthesized a significantly reduced amount of IFT52 protein, leading to reduced synthesis of IFT74, IFT81, IFT88 and ARL13B, other key anterograde complex members. Ciliogenesis was also disrupted in the mutant cells, with a 60% reduction in the presence of cilia on mutant cells and loss of cilia length regulation for the cells with cilia. These data demonstrate that IFT52 is essential for anterograde complex integrity and for the biosynthesis and maintenance of cilia. The data identify a new locus for SRPS and show that IFT52 mutations result in a ciliopathy with primary effects on the skeleton.

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