2. Academic Validation
  3. Mutations in IFT-A satellite core component genes IFT43 and IFT121 produce short rib polydactyly syndrome with distinctive campomelia

Mutations in IFT-A satellite core component genes IFT43 and IFT121 produce short rib polydactyly syndrome with distinctive campomelia

  • Cilia. 2017 Apr 10;6:7. doi: 10.1186/s13630-017-0051-y.
Ivan Duran 1 2,  S Paige Taylor 3,  Wenjuan Zhang 4,  Jorge Martin 1,  Faisal Qureshi 5,  Suzanne M Jacques 5,  Robert Wallerstein 6,  Ralph S Lachman 7,  Deborah A Nickerson 8,  Michael Bamshad 8,  Daniel H Cohn 1 4 7,  Deborah Krakow 1 3 9 7
Affiliations

Affiliations

  • 1 Department of Orthopaedic Surgery, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA 90095 USA.
  • 2 Networking Research Center on Bioengineering, Biomaterials and Nanomedicine, (CIBER-BBN), University of Malaga, Málaga, Spain.
  • 3 Department of Human Genetics, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA 90095 USA.
  • 4 Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095 USA.
  • 5 Department of Pathology, Hutzel Women's Hospital/Wayne State University, Detroit, MI 48201 USA.
  • 6 Kapi'olani Medical Center for Women and Children, Honolulu, HI 96826 USA.
  • 7 International Skeletal Dysplasia Registry, University of California, Los Angeles, Los Angeles, CA 90095 USA.
  • 8 University of Washington Center for Mendelian Genomics, University of Washington, Seattle, WA 98195 USA.
  • 9 Department of Obstetrics and Gynecology, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA 90095 USA.
PMID: 28400947 DOI: 10.1186/s13630-017-0051-y
Abstract

Background: Skeletal ciliopathies comprise a spectrum of ciliary malfunction disorders that have a profound effect on the skeleton. Most common among these disorders is short rib polydactyly syndrome (SRPS), a recessively inherited perinatal lethal condition characterized by a long narrow chest, markedly shortened long bones, polydactyly and, often, multi-organ system involvement. SRPS shows extensive locus heterogeneity with mutations in genes encoding proteins that participate in cilia formation and/or function.

Results: Herein we describe mutations in IFT43, a satellite member of the retrograde IFT-A complex, that produce a form of SRPS with unusual bending of the ribs and appendicular bones. These newly described IFT43 mutations disrupted cilia formation, produced abnormalities in cartilage growth plate architecture thus contributing to altered endochondral ossification. We further show that the IFT43 SRPS phenotype is similar to SRPS resulting from mutations in the gene encoding IFT121 (WDR35), a direct interactor with IFT43.

Conclusions: This study defines a new IFT43-associated phenotype, identifying an additional locus for SRPS. The data demonstrate that IFT43 is essential for ciliogenesis and that the mutations disrupted the orderly proliferation and differentiation of growth plate chondrocytes, resulting in a severe effect on endochondral ossification and mineralization. Phenotypic similarities with SRPS cases resulting from mutations in the gene encoding the IFT43 direct interacting protein IFT121 suggests that similar mechanisms may be disrupted by defects in these two IFT-A satellite interactors.

Keywords

Cartilage; Cilia; IFT; IFT-A complex; IFT121; IFT43; Intraflagellar transport; Retrograde transport; SRPS; Short rib polydactyly syndrome; Skeletal ciliopathy.

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