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Am J Hum Genet. 2014 Jan 2;94(1):62-72. doi: 10.1016/j.ajhg.2013.11.019. Epub 2013 Dec 19.

Mutations in CSPP1 cause primary cilia abnormalities and Joubert syndrome with or without Jeune asphyxiating thoracic dystrophy.

Author information

1
Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA.
2
Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland; Institute of Medical Genetics, University of Zurich, 8603 Zurich, Switzerland.
3
Divisions of Genetic Medicine and Developmental Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
4
Department of Molecular & Medical Genetics, Oregon Health Sciences University, Portland, OR 97239, USA.
5
Neurogenetics Division, Clinics Hospital, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo 14049-900, Brazil.
6
Department of Pediatrics, King Abdulaziz Medical City, Riyadh 11426, Saudi Arabia.
7
Neuromuscular and Neurogenetic Disorders of Childhood Section, John Edward Porter Neuroscience Research Center, National Institutes of Health, Bethesda, MD 20892, USA.
8
Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
9
Department of Pediatric Genetics, Amrita Institute of Medical Sciences and Research Center, AIMS Ponekkara Post Office, Kochi, Kerala 682041, India.
10
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Parkville, VIC 3052, Australia.
11
Departments of Neurology and Pediatrics, Murdoch Childrens Research Institute, Royal Children's Hospital and University of Melbourne, Parkville, VIC 3052, Australia.
12
Department of Child Neurology, Hacettepe University Medical Faculty, Ihsan Dogramacı Children's Hospital, Ankara 06100, Turkey.
13
Pediatric Neurology Unit, De Karadeniz Technical University, Trabzon 61080, Turkey.
14
MediScan Systems, Mylapore, Chennai 600 004, India.
15
Department of Radiology, University of Washington and Seattle Children's Hospital, Seattle, WA 98105, USA.
16
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.
17
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
18
Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
19
Department of Pediatrics, Section on Medical Genetics, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
20
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.
21
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.

Erratum in

  • Am J Hum Genet. 2014 Feb 6;94(2):310.

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.

PMID:
24360808
PMCID:
PMC3882733
DOI:
10.1016/j.ajhg.2013.11.019
[Indexed for MEDLINE]
Free PMC Article

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