title: Mutations in CSPP1, encoding a core centrosomal protein, cause a range of ciliopathy phenotypes in humans.
abstract: Ciliopathies are characterized by a pattern of multisystem involvement that is consistent with the developmental role of the primary cilium. Within this biological module, mutations in genes that encode components of the cilium and its anchoring structure, the basal body, are the major contributors to both disease causality and modification. However, despite rapid advances in this field, the majority of the genes that drive ciliopathies and the mechanisms that govern the pronounced phenotypic variability of this group of disorders remain poorly understood. Here, we show that mutations in CSPP1, which encodes a core centrosomal protein, are disease causing on the basis of the independent identification of two homozygous truncating mutations in three consanguineous families (one Arab and two Hutterite) affected by variable ciliopathy phenotypes ranging from Joubert syndrome to the more severe Meckel-Gruber syndrome with perinatal lethality and occipital encephalocele. Consistent with the recently described role of CSPP1 in ciliogenesis, we show that mutant fibroblasts from one affected individual have severely impaired ciliogenesis with concomitant defects in sonic hedgehog (SHH) signaling. Our results expand the list of centrosomal proteins implicated in human ciliopathies.
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital, Riyadh 11211, Saudi Arabia.
authors.forename: Ranad
authors.initials: R
authors.lastname: Shaheen
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital, Riyadh 11211, Saudi Arabia.
authors.forename: Hanan E
authors.initials: HE
authors.lastname: Shamseldin
authors.affiliation: Department of Medical Genetics, University of Calgary, Alberta Children's Hospital, Calgary, AB T3B 6A8, Canada.
authors.forename: Catrina M
authors.initials: CM
authors.lastname: Loucks
authors.affiliation: Department of Pediatrics, Security Forces Hospital, Riyadh 11481, Saudi Arabia.
authors.forename: Mohammed Zain
authors.initials: MZ
authors.lastname: Seidahmed
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital, Riyadh 11211, Saudi Arabia.
authors.forename: Shinu
authors.initials: S
authors.lastname: Ansari
authors.affiliation: Department of Obstetrics and Gynecology, Security Forces Hospital, Riyadh 11481, Saudi Arabia.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Ibrahim Khalil
authors.affiliation: Cardiovascular Research Program, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Nadya
authors.initials: N
authors.lastname: Al-Yacoub
authors.affiliation: Center for Human Disease Modeling, Duke University, Durham, NC 22710, USA.
authors.forename: Erica E
authors.initials: EE
authors.lastname: Davis
authors.affiliation: Center for Human Disease Modeling, Duke University, Durham, NC 22710, USA.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Mola
authors.affiliation: Leeds Institute of Molecular Medicine, St. James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Szymanska
authors.affiliation: Leeds Institute of Molecular Medicine, St. James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK.
authors.forename: Warren
authors.initials: W
authors.lastname: Herridge
authors.affiliation: Department of Paediatrics and Child Health and Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB R3A 1R9, Canada.
authors.forename: Albert E
authors.initials: AE
authors.lastname: Chudley
authors.affiliation: Department of Paediatrics and Child Health and Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB R3A 1R9, Canada.
authors.forename: Bernard N
authors.initials: BN
authors.lastname: Chodirker
authors.affiliation: McGill University and Genome Quebec Innovation Center, Montreal, QC H3A 0G4, Canada.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schwartzentruber
authors.affiliation: McGill University and Genome Quebec Innovation Center, Montreal, QC H3A 0G4, Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Center for Human Disease Modeling, Duke University, Durham, NC 22710, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.affiliation: Cardiovascular Research Program, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Coralie
authors.initials: C
authors.lastname: Poizat
authors.affiliation: Leeds Institute of Molecular Medicine, St. James's University Hospital, Beckett Street, Leeds, West Yorkshire LS9 7TF, UK.
authors.forename: Colin A
authors.initials: CA
authors.lastname: Johnson
authors.affiliation: Department of Medical Genetics, University of Calgary, Alberta Children's Hospital, Calgary, AB T3B 6A8, Canada; Alberta Children's Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, AB T3B 6A8, Canada.
authors.forename: Jillian
authors.initials: J
authors.lastname: Parboosingh
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
authors.affiliation: Department of Medical Genetics, University of Calgary, Alberta Children's Hospital, Calgary, AB T3B 6A8, Canada; Alberta Children's Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, AB T3B 6A8, Canada. Electronic address: micheil.innes@albertahealthservices.ca.
authors.forename: A Micheil
authors.initials: AM
authors.lastname: Innes
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital, Riyadh 11211, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia. Electronic address: falkuraya@kfshrc.edu.sa.
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D000015:Abnormalities, Multiple; D018797:Cell Cycle Proteins / Q000235:genetics*; D018385:Centrosome / Q000378:metabolism*; D002526:Cerebellar Diseases / Q000235:genetics; D002531:Cerebellum / Q000002:abnormalities; D002648:Child; D002923:Cilia / Q000235:genetics / Q000473:pathology*; D002925:Ciliary Motility Disorders / Q000235:genetics; D003241:Consanguinity; D004677:Encephalocele / Q000235:genetics; D005124:Eye Abnormalities / Q000235:genetics; D005260:Female; D006720:Homozygote; D006801:Humans; D007223:Infant; D052177:Kidney Diseases, Cystic / Q000235:genetics; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D007690:Polycystic Kidney Diseases / Q000235:genetics; D012160:Retina / Q000002:abnormalities; D012174:Retinitis Pigmentosa; D015398:Signal Transduction
chemical_list: C514207:CSPP1 protein, human; D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins