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

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  • S. Paige Taylor

    (University of California, Los Angeles)

  • Tiago J. Dantas

    (Columbia University)

  • Ivan Duran

    (University of California, Los Angeles)

  • Sulin Wu

    (University of California, Los Angeles)

  • Ralph S. Lachman

    (International Skeletal Dysplasia Registry, University of California, Los Angeles)

  • Stanley F. Nelson

    (University of California, Los Angeles
    University of California, Los Angeles)

  • Daniel H. Cohn

    (University of California, Los Angeles
    International Skeletal Dysplasia Registry, University of California, Los Angeles
    Cell, and Developmental Biology, University of California, Los Angeles)

  • Richard B. Vallee

    (Columbia University)

  • Deborah Krakow

    (University of California, Los Angeles
    University of California, Los Angeles
    International Skeletal Dysplasia Registry, University of California, Los Angeles)

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.

Suggested Citation

  • S. Paige Taylor & Tiago J. Dantas & Ivan Duran & Sulin Wu & Ralph S. Lachman & Stanley F. Nelson & Daniel H. Cohn & Richard B. Vallee & Deborah Krakow, 2015. "Mutations in DYNC2LI1 disrupt cilia function and cause short rib polydactyly syndrome," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8092
    DOI: 10.1038/ncomms8092
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