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

TitleIFT52 mutations destabilize anterograde complex assembly, disrupt ciliogenesis and result in short rib polydactyly syndrome.
Publication TypeJournal Article
Year of Publication2016
AuthorsZhang, W, S Taylor, P, Nevarez, L, Lachman, RS, Nickerson, DA, Bamshad, M, Krakow, D, Cohn, DH
Corporate AuthorsUniversity of Washington Center for Mendelian Genomics Consortium
JournalHum Mol Genet
Volume25
Issue18
Pagination4012-4020
Date Published2016 09 15
ISSN1460-2083
KeywordsCarrier Proteins, Cilia, Ciliopathies, Cytoskeletal Proteins, Flagella, Humans, 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.

DOI10.1093/hmg/ddw241
Alternate JournalHum. Mol. Genet.
PubMed ID27466190
PubMed Central IDPMC5291235
Grant ListU54 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