Year: 2015
Type: article
Abstract: The short rib polydactyly syndromes (SRPSs) are a heterogeneous group of autosomal recessive, perinatal lethal skeletal disorders characterized primarily by short, horizontal ribs, short limbs and polydactyly. Mutations in several genes affecting intraflagellar transport (IFT) cause SRPS but they do not account for all cases. Here we identify an additional SRPS gene and further unravel the functional basis for IFT. We perform whole-exome sequencing and identify mutations in a new disease-producing gene, cytoplasmic dynein-2 light intermediate chain 1, DYNC2LI1, segregating with disease in three families. Using primary fibroblasts, we show that DYNC2LI1 is essential for dynein-2 complex stability and that mutations in DYNC2LI1 result in variable length, including hyperelongated, cilia, Hedgehog pathway impairment and ciliary IFT accumulations. The findings in this study expand our understanding of SRPS locus heterogeneity and demonstrate the importance of DYNC2LI1 in dynein-2 complex stability, cilium function, Hedgehog regulation and skeletogenesis. Mutations in genes affecting intraflagellar transport account for some but not all cases of short rib polydactyly syndromes. Here Taylor et al. use whole exome sequencing and in vivo cell line assays to identify novel disease associated mutations in DYNC2LI1.
Source: Nature Communications
DOI: 10.1038/ncomms8092
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: National Science Foundation, March of Dimes Foundation, University of Washington, National Institutes of Health, U.S. Public Health Service, National Human Genome Research Institute, National Institute of General Medical Sciences, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Research Resources, Division of Chemistry, Center for Substance Abuse Prevention, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Clinical and Translational Science Institute, University of California, Los Angeles, California NanoSystems Institute
Awards: G1068064772, G1545794908, G2469622367, Mechanism of Action of Dynactin, UCLA Clinical and Translational Science Institute, Motor Proteins in Brain Development, G4218214233, G4578215389, G4678343919, Exome sequencing in the skeletal dysplasias, UW Center for Mendelian Genomics, G4960220192, G519369007, UCLA Muscular Dystrophy Core Center, Unraveling the mechanisms of prenatal-onset disorders affecting the skeleton, G6082311035, G6952614038, G7114678960, G7311987857, MRI: Acquisition of a Stimulated Emission Depletion (STED) Microscope for Nanoscopic Resolution of Biological Samples, UCLA Clinical and Translational Science Institute, G814417867, UW Center for Mendelian Genomics, G9000343091, G9000345790, Training Grant in Genomic Analysis and Interpretation
OpenAlex ID: W2260102155