title: Mutations in CSPP1 cause primary cilia abnormalities and Joubert syndrome with or without Jeune asphyxiating thoracic dystrophy.
abstract: Joubert syndrome (JBTS) is a recessive ciliopathy in which a subset of affected individuals also have the skeletal dysplasia Jeune asphyxiating thoracic dystrophy (JATD). Here, we have identified biallelic truncating CSPP1 (centrosome and spindle pole associated protein 1) mutations in 19 JBTS-affected individuals, four of whom also have features of JATD. CSPP1 mutations explain ∼5% of JBTS in our cohort, and despite truncating mutations in all affected individuals, the range of phenotypic severity is broad. Morpholino knockdown of cspp1 in zebrafish caused phenotypes reported in other zebrafish models of JBTS (curved body shape, pronephric cysts, and cerebellar abnormalities) and reduced ciliary localization of Arl13b, further supporting loss of CSPP1 function as a cause of JBTS. Fibroblasts from affected individuals with CSPP1 mutations showed reduced numbers of primary cilia and/or short primary cilia, as well as reduced axonemal localization of ciliary proteins ARL13B and adenylyl cyclase III. In summary, CSPP1 mutations are a major cause of the Joubert-Jeune phenotype in humans; however, the mechanism by which these mutations lead to both JBTS and JATD remains unknown.
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Karina
authors.initials: K
authors.lastname: Tuz
authors.affiliation: Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland; Institute of Medical Genetics, University of Zurich, 8603 Zurich, Switzerland.
authors.forename: Ruxandra
authors.initials: R
authors.lastname: Bachmann-Gagescu
authors.affiliation: Divisions of Genetic Medicine and Developmental Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Diana R
authors.initials: DR
authors.lastname: O'Day
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Kiet
authors.initials: K
authors.lastname: Hua
authors.affiliation: Divisions of Genetic Medicine and Developmental Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Christine R
authors.initials: CR
authors.lastname: Isabella
authors.affiliation: Divisions of Genetic Medicine and Developmental Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Ian G
authors.initials: IG
authors.lastname: Phelps
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA.
authors.forename: Allan E
authors.initials: AE
authors.lastname: Stolarski
authors.affiliation: Department of Molecular & Medical Genetics, Oregon Health Sciences University, Portland, OR 97239, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: O'Roak
authors.affiliation: Divisions of Genetic Medicine and Developmental Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Dempsey
authors.affiliation: Neurogenetics Division, Clinics Hospital, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo 14049-900, Brazil.
authors.forename: Charles
authors.initials: C
authors.lastname: Lourenco
authors.affiliation: Department of Pediatrics, King Abdulaziz Medical City, Riyadh 11426, Saudi Arabia.
authors.forename: Abdulrahman
authors.initials: A
authors.lastname: Alswaid
authors.affiliation: Neuromuscular and Neurogenetic Disorders of Childhood Section, John Edward Porter Neuroscience Research Center, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Carsten G
authors.initials: CG
authors.lastname: Bönnemann
authors.affiliation: Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Livija
authors.initials: L
authors.lastname: Medne
authors.affiliation: Department of Pediatric Genetics, Amrita Institute of Medical Sciences and Research Center, AIMS Ponekkara Post Office, Kochi, Kerala 682041, India.
authors.forename: Sheela
authors.initials: S
authors.lastname: Nampoothiri
authors.affiliation: Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Parkville, VIC 3052, Australia.
authors.forename: Zornitza
authors.initials: Z
authors.lastname: Stark
authors.affiliation: Departments of Neurology and Pediatrics, Murdoch Childrens Research Institute, Royal Children's Hospital and University of Melbourne, Parkville, VIC 3052, Australia.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Leventer
authors.affiliation: Department of Child Neurology, Hacettepe University Medical Faculty, Ihsan Dogramacı Children's Hospital, Ankara 06100, Turkey.
authors.forename: Meral
authors.initials: M
authors.lastname: Topçu
authors.affiliation: Pediatric Neurology Unit, De Karadeniz Technical University, Trabzon 61080, Turkey.
authors.forename: Ali
authors.initials: A
authors.lastname: Cansu
authors.affiliation: MediScan Systems, Mylapore, Chennai 600 004, India.
authors.forename: Sujatha
authors.initials: S
authors.lastname: Jagadeesh
authors.affiliation: Department of Radiology, University of Washington and Seattle Children's Hospital, Seattle, WA 98105, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Done
authors.affiliation: Department of Radiology, University of Washington and Seattle Children's Hospital, Seattle, WA 98105, USA.
authors.forename: Gisele E
authors.initials: GE
authors.lastname: Ishak
authors.affiliation: Divisions of Genetic Medicine and Developmental Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Center for Integrative Brain Research, Seattle Children's Hospital Research Institute, Seattle, WA 98105, USA.
authors.forename: Ian A
authors.initials: IA
authors.lastname: Glass
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.affiliation: Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Stephan C F
authors.initials: SC
authors.lastname: Neuhauss
authors.affiliation: Department of Pediatrics, Section on Medical Genetics, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Chad R
authors.initials: CR
authors.lastname: Haldeman-Englert
authors.affiliation: Divisions of Genetic Medicine and Developmental Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Center for Integrative Brain Research, Seattle Children's Hospital Research Institute, Seattle, WA 98105, USA. Electronic address: ddoher@uw.edu.
authors.forename: Dan
authors.initials: D
authors.lastname: Doherty
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA; Department of Neurology, Albany Medical College, Albany, NY 12208, USA. Electronic address: ferlanr@mail.amc.edu.
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Ferland
mesh_terms: D000015:Abnormalities, Multiple; D000293:Adolescent; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D002526:Cerebellar Diseases / Q000235:genetics*; D002531:Cerebellum / Q000002:abnormalities; D002648:Child; D002675:Child, Preschool; D002923:Cilia / Q000235:genetics* / Q000473:pathology; D004613:Ellis-Van Creveld Syndrome / Q000235:genetics*; D005091:Exons; D005124:Eye Abnormalities / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D007223:Infant; D052177:Kidney Diseases, Cystic / Q000235:genetics*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D012160:Retina / Q000002:abnormalities*; D017422:Sequence Analysis, DNA; D055815:Young Adult; D015027:Zebrafish / Q000235:genetics
chemical_list: C514207:CSPP1 protein, human; D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins