Title | IFT52 mutations destabilize anterograde complex assembly, disrupt ciliogenesis and result in short rib polydactyly syndrome. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Zhang, W, S Taylor, P, Nevarez, L, Lachman, RS, Nickerson, DA, Bamshad, M, Krakow, D, Cohn, DH |
Corporate Authors | University of Washington Center for Mendelian Genomics Consortium |
Journal | Hum Mol Genet |
Volume | 25 |
Issue | 18 |
Pagination | 4012-4020 |
Date Published | 2016 Sep 15 |
ISSN | 1460-2083 |
Keywords | Carrier Proteins, Cilia, Ciliopathies, Cytoskeletal Proteins, Flagella, Humans, Intracellular Signaling Peptides and Proteins, Multiprotein Complexes, Muscle Proteins, Mutation, Short Rib-Polydactyly Syndrome, Skeleton, Tumor Suppressor Proteins |
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. |
DOI | 10.1093/hmg/ddw241 |
Alternate Journal | Hum Mol Genet |
PubMed ID | 27466190 |
PubMed Central ID | PMC5291235 |
Grant List | U54 HG006493 / HG / NHGRI NIH HHS / United States T32 HG002536 / HG / NHGRI NIH HHS / United States UL1 TR000124 / TR / NCATS NIH HHS / United States UM1 HG006493 / HG / NHGRI NIH HHS / United States R01 AR066124 / AR / NIAMS NIH HHS / United States R01 AR062651 / AR / NIAMS NIH HHS / United States |