title: Mutations in DYNC2LI1 disrupt cilia function and cause short rib polydactyly syndrome.
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.
authors.affiliation: Department of Human Genetics, University of California, Los Angeles, Los Angeles, California 90095, USA.
authors.forename: S Paige
authors.initials: SP
authors.lastname: Taylor
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA.
authors.forename: Tiago J
authors.initials: TJ
authors.lastname: Dantas
authors.affiliation: Department of Orthopaedic Surgery and Orthopaedic Institute for Children, University of California, Los Angeles, Los Angeles, California 90095, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Duran
authors.affiliation: Department of Orthopaedic Surgery and Orthopaedic Institute for Children, University of California, Los Angeles, Los Angeles, California 90095, USA.
authors.forename: Sulin
authors.initials: S
authors.lastname: Wu
authors.affiliation: International Skeletal Dysplasia Registry, University of California, Los Angeles, Los Angeles, California 90095, USA.
authors.forename: Ralph S
authors.initials: RS
authors.lastname: Lachman
authors.affiliation: 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.
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
authors.affiliation: 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.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Cohn
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Vallee
authors.affiliation: 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.
authors.forename: Deborah
authors.initials: D
authors.lastname: Krakow
mesh_terms: D001692:Biological Transport / Q000235:genetics; D002923:Cilia / Q000378:metabolism*; D056445:Cytoplasmic Dyneins / Q000235:genetics*; D003599:Cytoskeleton / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D005407:Flagella / Q000378:metabolism; D053823:Hedgehog Proteins; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D012779:Short Rib-Polydactyly Syndrome / Q000235:genetics*
chemical_list: D053823:Hedgehog Proteins; D056445:Cytoplasmic Dyneins; C000606394:DYNC2LI1 protein, human