2. Academic Validation
  3. Mutations in DYNC2LI1 disrupt cilia function and cause short rib polydactyly syndrome

Mutations in DYNC2LI1 disrupt cilia function and cause short rib polydactyly syndrome

  • Nat Commun. 2015 Jun 16;6:7092. doi: 10.1038/ncomms8092.
S Paige Taylor 1,  Tiago J Dantas 2,  Ivan Duran 3,  Sulin Wu 3,  Ralph S Lachman 4,  University of Washington Center for Mendelian Genomics Consortium,  Stanley F Nelson 7,  Daniel H Cohn 8,  Richard B Vallee 2,  Deborah Krakow 9
Affiliations

Affiliations

  • 1 Department of Human Genetics, University of California, Los Angeles, Los Angeles, California 90095, USA.
  • 2 Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA.
  • 3 Department of Orthopaedic Surgery and Orthopaedic Institute for Children, University of California, Los Angeles, Los Angeles, California 90095, USA.
  • 4 International Skeletal Dysplasia Registry, University of California, Los Angeles, Los Angeles, California 90095, USA.
  • 5 Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA.
  • 6 Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
  • 7 1] Department of Human Genetics, University of California, Los Angeles, Los Angeles, California 90095, USA [2] Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA.
  • 8 1] Department of Orthopaedic Surgery and Orthopaedic Institute for Children, University of California, Los Angeles, Los Angeles, California 90095, USA [2] International Skeletal Dysplasia Registry, University of California, Los Angeles, Los Angeles, California 90095, USA [3] Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, California 90095, USA.
  • 9 1] Department of Human Genetics, University of California, Los Angeles, Los Angeles, California 90095, USA [2] Department of Orthopaedic Surgery and Orthopaedic Institute for Children, University of California, Los Angeles, Los Angeles, California 90095, USA [3] International Skeletal Dysplasia Registry, University of California, Los Angeles, Los Angeles, California 90095, USA.
PMID: 26077881 DOI: 10.1038/ncomms8092
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.

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