title: IFT52 mutations destabilize anterograde complex assembly, disrupt ciliogenesis and result in short rib polydactyly syndrome.
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.
authors.affiliation: Department of Molecular, Cell, and Developmental Biology.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Human Genetics.
authors.forename: S Paige
authors.initials: SP
authors.lastname: Taylor
authors.affiliation: Department of Molecular, Cell, and Developmental Biology.
authors.forename: Lisette
authors.initials: L
authors.lastname: Nevarez
authors.affiliation: International Skeletal Dysplasia Registry, University of California, Los Angeles, California, USA.
authors.forename: Ralph S
authors.initials: RS
authors.lastname: Lachman
authors.affiliation: Department of Genome Sciences.|University of Washington Center for Mendelian Genomics.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.affiliation: Department of Genome Sciences.|University of Washington Center for Mendelian Genomics.|Department of Pediatrics, University of Washington, Seattle, Washington, USA.|Division of Genetic Medicine, Seattle Children's Hospital, Seattle, Washington, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Bamshad
authors.affiliation: Department of Human Genetics.|International Skeletal Dysplasia Registry, University of California, Los Angeles, California, USA.|Department of Obstetrics and Gynecology.|Department of Orthopaedic Surgery and Orthopaedic Hospital Research Center, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Krakow
authors.affiliation: Department of Molecular, Cell, and Developmental Biology dcohn@mcdb.ucla.edu.|International Skeletal Dysplasia Registry, University of California, Los Angeles, California, USA.|Department of Orthopaedic Surgery and Orthopaedic Hospital Research Center, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.|Department of Molecular, Cell, and Developmental Biology.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Cohn
mesh_terms: D002352:Carrier Proteins / Q000235:genetics*; D002923:Cilia / Q000235:genetics* / Q000378:metabolism; D000072661:Ciliopathies / Q000235:genetics* / Q000503:physiopathology; D003598:Cytoskeletal Proteins / Q000235:genetics; D005407:Flagella / Q000235:genetics / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics; D009154:Mutation / Q000235:genetics; D012779:Short Rib-Polydactyly Syndrome / Q000235:genetics* / Q000503:physiopathology; D012863:Skeleton / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C000621073:IFT52 protein, human; C490080:IFT74 protein, human; C481012:IFT81 protein, human; C098623:IFT88 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D009124:Muscle Proteins; D025521:Tumor Suppressor Proteins