title: DYNC2LI1 mutations broaden the clinical spectrum of dynein-2 defects.
abstract: Skeletal ciliopathies are a heterogeneous group of autosomal recessive osteochondrodysplasias caused by defects in formation, maintenance and function of the primary cilium. Mutations in the underlying genes affect the molecular motors, intraflagellar transport complexes (IFT), or the basal body. The more severe phenotypes are caused by defects of genes of the dynein-2 complex, where mutations in DYNC2H1, WDR34 and WDR60 have been identified. In a patient with a Jeune-like phenotype we performed exome sequencing and identified compound heterozygous missense and nonsense mutations in DYNC2LI1 segregating with the phenotype. DYNC2LI1 is ubiquitously expressed and interacts with DYNC2H1 to form the dynein-2 complex important for retrograde IFT. Using DYNC2LI1 siRNA knockdown in fibroblasts we identified a significantly reduced cilia length proposed to affect cilia function. In addition, depletion of DYNC2LI1 induced altered cilia morphology with broadened ciliary tips and accumulation of IFT-B complex proteins in accordance with retrograde IFT defects. Our results expand the clinical spectrum of ciliopathies caused by defects of the dynein-2 complex.
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Kessler
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Wunderlich
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Uebe
authors.affiliation: Animal Physiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Nathalie S
authors.initials: NS
authors.lastname: Falk
authors.affiliation: Animal Physiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Gießl
authors.affiliation: Animal Physiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Johann Helmut
authors.initials: JH
authors.lastname: Brandstätter
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Bernt
authors.initials: B
authors.lastname: Popp
authors.affiliation: Department of Orthopaedic Rheumatology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Patricia
authors.initials: P
authors.lastname: Klinger
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Arif B
authors.initials: AB
authors.lastname: Ekici
authors.affiliation: Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Sticht
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Helmuth-Günther
authors.initials: HG
authors.lastname: Dörr
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: Roepman
authors.affiliation: Department of Clinical Genetics, Institute of Biology and Medical Genetics, 2nd Medical School, Charles University, Prague, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Seemanová
authors.affiliation: Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Christian T
authors.initials: CT
authors.lastname: Thiel
mesh_terms: D002923:Cilia / Q000378:metabolism; D018389:Codon, Nonsense / Q000235:genetics; D056445:Cytoplasmic Dyneins / Q000737:chemistry / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006579:Heterozygote; D006801:Humans; D009154:Mutation / Q000235:genetics*; D017434:Protein Structure, Tertiary; D017422:Sequence Analysis, DNA
chemical_list: D018389:Codon, Nonsense; D056445:Cytoplasmic Dyneins; C000606394:DYNC2LI1 protein, human