title: Mutations in CSPP1 lead to classical Joubert syndrome.
abstract: Joubert syndrome and related disorders (JSRDs) are genetically heterogeneous and characterized by a distinctive mid-hindbrain malformation. Causative mutations lead to primary cilia dysfunction, which often results in variable involvement of other organs such as the liver, retina, and kidney. We identified predicted null mutations in CSPP1 in six individuals affected by classical JSRDs. CSPP1 encodes a protein localized to centrosomes and spindle poles, as well as to the primary cilium. Despite the known interaction between CSPP1 and nephronophthisis-associated proteins, none of the affected individuals in our cohort presented with kidney disease, and further, screening of a large cohort of individuals with nephronophthisis demonstrated no mutations. CSPP1 is broadly expressed in neural tissue, and its encoded protein localizes to the primary cilium in an in vitro model of human neurogenesis. Here, we show abrogated protein levels and ciliogenesis in affected fibroblasts. Our data thus suggest that CSPP1 is involved in neural-specific functions of primary cilia.
authors.affiliation: Neurogenetics Laboratory, Institute for Genomic Medicine and Departments of Neurosciences and Pediatrics, University of California, San Diego, San Diego, CA 92093, USA; Howard Hughes Medical Institute.
authors.forename: Naiara
authors.initials: N
authors.lastname: Akizu
authors.affiliation: Neurogenetics Laboratory, Institute for Genomic Medicine and Departments of Neurosciences and Pediatrics, University of California, San Diego, San Diego, CA 92093, USA; Howard Hughes Medical Institute.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Silhavy
authors.affiliation: Neurogenetics Laboratory, Institute for Genomic Medicine and Departments of Neurosciences and Pediatrics, University of California, San Diego, San Diego, CA 92093, USA; Howard Hughes Medical Institute.
authors.forename: Rasim Ozgur
authors.initials: RO
authors.lastname: Rosti
authors.affiliation: Neurogenetics Laboratory, Institute for Genomic Medicine and Departments of Neurosciences and Pediatrics, University of California, San Diego, San Diego, CA 92093, USA; Howard Hughes Medical Institute.
authors.forename: Eric
authors.initials: E
authors.lastname: Scott
authors.affiliation: Neurogenetics Laboratory, Institute for Genomic Medicine and Departments of Neurosciences and Pediatrics, University of California, San Diego, San Diego, CA 92093, USA; Howard Hughes Medical Institute.
authors.forename: Ali G
authors.initials: AG
authors.lastname: Fenstermaker
authors.affiliation: Neurogenetics Laboratory, Institute for Genomic Medicine and Departments of Neurosciences and Pediatrics, University of California, San Diego, San Diego, CA 92093, USA; Howard Hughes Medical Institute.
authors.forename: Jana
authors.initials: J
authors.lastname: Schroth
authors.affiliation: Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
authors.forename: Maha S
authors.initials: MS
authors.lastname: Zaki
authors.affiliation: Pediatrics Department, Palo Alto Medical Foundation, Fremont, CA 94538, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: Sanchez
authors.affiliation: Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi 110029, India.
authors.forename: Neerja
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi 110029, India.
authors.forename: Madhulika
authors.initials: M
authors.lastname: Kabra
authors.affiliation: Department of Pediatrics, Tripoli Children's Hospital, PO Box 2214, Tripoli, Libya.
authors.forename: Majdi
authors.initials: M
authors.lastname: Kara
authors.affiliation: Clinical and Metabolic Genetics Division, Department of Pediatrics, Hamad Medical Corporation, Doha 3050, Qatar.
authors.forename: Tawfeg
authors.initials: T
authors.lastname: Ben-Omran
authors.affiliation: Neurogenetics Laboratory, Institute for Genomic Medicine and Departments of Neurosciences and Pediatrics, University of California, San Diego, San Diego, CA 92093, USA; Howard Hughes Medical Institute.
authors.forename: Basak
authors.initials: B
authors.lastname: Rosti
authors.affiliation: Neurogenetics Laboratory, Institute for Genomic Medicine and Departments of Neurosciences and Pediatrics, University of California, San Diego, San Diego, CA 92093, USA; Howard Hughes Medical Institute.
authors.forename: Alicia
authors.initials: A
authors.lastname: Guemez-Gamboa
authors.affiliation: Neurogenetics Laboratory, Institute for Genomic Medicine and Departments of Neurosciences and Pediatrics, University of California, San Diego, San Diego, CA 92093, USA; Howard Hughes Medical Institute.
authors.forename: Emily
authors.initials: E
authors.lastname: Spencer
authors.affiliation: Neurogenetics Laboratory, Institute for Genomic Medicine and Departments of Neurosciences and Pediatrics, University of California, San Diego, San Diego, CA 92093, USA; Howard Hughes Medical Institute.
authors.forename: Roger
authors.initials: R
authors.lastname: Pan
authors.affiliation: Neurogenetics Laboratory, Institute for Genomic Medicine and Departments of Neurosciences and Pediatrics, University of California, San Diego, San Diego, CA 92093, USA; Howard Hughes Medical Institute.
authors.forename: Na
authors.initials: N
authors.lastname: Cai
authors.affiliation: Neurogenetics Laboratory, Institute for Genomic Medicine and Departments of Neurosciences and Pediatrics, University of California, San Diego, San Diego, CA 92093, USA; Howard Hughes Medical Institute.
authors.forename: Mostafa
authors.initials: M
authors.lastname: Abdellateef
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA 02141, USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Gabriel
authors.affiliation: Howard Hughes Medical Institute; Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Halbritter
authors.affiliation: Howard Hughes Medical Institute; Division of Nephrology, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, 6500 HB Nijmegen, the Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.affiliation: Yale Program on Neurogenetics, Departments of Neurosurgery, Neurobiology, and Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Murat
authors.initials: M
authors.lastname: Gunel
authors.affiliation: Neurogenetics Laboratory, Institute for Genomic Medicine and Departments of Neurosciences and Pediatrics, University of California, San Diego, San Diego, CA 92093, USA; Howard Hughes Medical Institute. Electronic address: jogleeson@ucsd.edu.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
mesh_terms: D000015:Abnormalities, Multiple; D001921:Brain / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D018385:Centrosome / Q000378:metabolism; D002526:Cerebellar Diseases / Q000235:genetics*; D002531:Cerebellum / Q000002:abnormalities; D002923:Cilia / Q000235:genetics / Q000473:pathology; D015331:Cohort Studies; D005124:Eye Abnormalities / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D007091:Image Processing, Computer-Assisted; D052177:Kidney Diseases, Cystic / Q000235:genetics*; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012160:Retina / Q000002:abnormalities*
chemical_list: C514207:CSPP1 protein, human; D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins