title: Mutations in IFT-A satellite core component genesIFT43andIFT121produce short rib polydactyly syndrome with distinctive campomelia.
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 inIFT43, 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 describedIFT43mutations disrupted cilia formation, produced abnormalities in cartilage growth plate architecture thus contributing to altered endochondral ossification. We further show that theIFT43SRPS phenotype is similar to SRPS resulting from mutations in the gene encoding IFT121 (WDR35), a direct interactor with IFT43.
  
  
  CONCLUSIONS
  This study defines a newIFT43-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.
authors.affiliation: Department of Orthopaedic Surgery, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA 90095 USA.|Networking Research Center on Bioengineering, Biomaterials and Nanomedicine, (CIBER-BBN), University of Malaga, Málaga, Spain.
authors.forename: Ivan
authors.initials: I
authors.lastname: Duran
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA 90095 USA.
authors.forename: S Paige
authors.initials: SP
authors.lastname: Taylor
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095 USA.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Orthopaedic Surgery, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA 90095 USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Martin
authors.affiliation: Department of Pathology, Hutzel Women's Hospital/Wayne State University, Detroit, MI 48201 USA.
authors.forename: Faisal
authors.initials: F
authors.lastname: Qureshi
authors.affiliation: Department of Pathology, Hutzel Women's Hospital/Wayne State University, Detroit, MI 48201 USA.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Jacques
authors.affiliation: Kapi'olani Medical Center for Women and Children, Honolulu, HI 96826 USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Wallerstein
authors.affiliation: International Skeletal Dysplasia Registry, University of California, Los Angeles, Los Angeles, CA 90095 USA.
authors.forename: Ralph S
authors.initials: RS
authors.lastname: Lachman
authors.affiliation: University of Washington Center for Mendelian Genomics, University of Washington, Seattle, WA 98195 USA.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.affiliation: University of Washington Center for Mendelian Genomics, University of Washington, Seattle, WA 98195 USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Bamshad
authors.affiliation: Department of Orthopaedic Surgery, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA 90095 USA.|Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095 USA.|International Skeletal Dysplasia Registry, University of California, Los Angeles, Los Angeles, CA 90095 USA.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Cohn
authors.affiliation: Department of Orthopaedic Surgery, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA 90095 USA.|Department of Human Genetics, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA 90095 USA.|Department of Obstetrics and Gynecology, David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA 90095 USA.|International Skeletal Dysplasia Registry, University of California, Los Angeles, Los Angeles, CA 90095 USA.
authors.forename: Deborah
authors.identifier: 0000-0001-9906-4968
authors.initials: D
authors.lastname: Krakow
keywords: Cartilage; Cilia; IFT; IFT-A complex; IFT121; IFT43; Intraflagellar transport; Retrograde transport; SRPS; Short rib polydactyly syndrome; Skeletal ciliopathy