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

S. Paige Taylor, Tiago J. Dantas, Ivan Duran, Sulin Wu, Ralph S. Lachman, Stanley F. Nelson, Daniel H. Cohn, Richard B. Vallee and Deborah Krakow ()
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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
Daniel H. Cohn: University of California, Los Angeles
Richard B. Vallee: Columbia University
Deborah Krakow: University of California, Los Angeles

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8092

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