title: A founder CEP120 mutation in Jeune asphyxiating thoracic dystrophy expands the role of centriolar proteins in skeletal ciliopathies.
abstract: Jeune asphyxiating thoracic dystrophy (JATD) is a skeletal dysplasia characterized by a small thoracic cage and a range of skeletal and extra-skeletal anomalies. JATD is genetically heterogeneous with at least nine genes identified, all encoding ciliary proteins, hence the classification of JATD as a skeletal ciliopathy. Consistent with the observation that the heterogeneous molecular basis of JATD has not been fully determined yet, we have identified two consanguineous Saudi families segregating JATD who share a single identical ancestral homozygous haplotype among the affected members. Whole-exome sequencing revealed a single novel variant within the disease haplotype in CEP120, which encodes a core centriolar protein. Subsequent targeted sequencing of CEP120 in Saudi and European JATD cohorts identified two additional families with the same missense mutation. Combining the four families in linkage analysis confirmed a significant genome-wide linkage signal at the CEP120 locus. This missense change alters a highly conserved amino acid within CEP120 (p.Ala199Pro). In addition, we show marked reduction of cilia and abnormal number of centrioles in fibroblasts from one affected individual. Inhibition of the CEP120 ortholog in zebrafish produced pleiotropic phenotypes characteristic of cilia defects including abnormal body curvature, hydrocephalus, otolith defects and abnormal renal, head and craniofacial development. We also demonstrate that in CEP120 morphants, cilia are shortened in the neural tube and disorganized in the pronephros. These results are consistent with aberrant CEP120 being implicated in the pathogenesis of JATD and expand the role of centriolar proteins in skeletal ciliopathies.
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Ranad
authors.initials: R
authors.lastname: Shaheen
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK, Department of Human Genetics, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, 6500 HB Nijmegen, the Netherlands.
authors.forename: Miriam
authors.initials: M
authors.lastname: Schmidts
authors.affiliation: Department of Pediatrics, King Fahad Medical City, Riyadh 59046, Saudi Arabia.
authors.forename: Eissa
authors.initials: E
authors.lastname: Faqeih
authors.affiliation: Department of Pediatrics, Prince Sultan Military Medical City, Riyadh 11159, Saudi Arabia.
authors.forename: Amal
authors.initials: A
authors.lastname: Hashem
authors.affiliation: Pediatric Genetics Division, Center for Adolescent and Pediatric Medicine, University Hospital Freiburg, Freiburg 79108, Germany.
authors.forename: Ekkehart
authors.initials: E
authors.lastname: Lausch
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Isabel
authors.initials: I
authors.lastname: Holder
authors.affiliation: Department of Pediatrics, Lausanne University Hospital, University of Lausanne, Lausanne 1011, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Mitchison
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Agaadir
authors.initials: A
authors.lastname: Almoisheer
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Rana
authors.initials: R
authors.lastname: Alamro
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Tarfa
authors.initials: T
authors.lastname: Alshiddi
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
authors.forename: Fatma
authors.initials: F
authors.lastname: Alzahrani
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK, falkuraya@kfshrc.edu.sa p.beales@ucl.ac.uk.
authors.forename: Philip L
authors.initials: PL
authors.lastname: Beales
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia, Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia falkuraya@kfshrc.edu.sa p.beales@ucl.ac.uk.
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002502:Centrioles / Q000235:genetics* / Q000378:metabolism; D002874:Chromosome Mapping; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics / Q000378:metabolism; D002923:Cilia / Q000473:pathology; D015331:Cohort Studies; D004195:Disease Models, Animal; D004613:Ellis-Van Creveld Syndrome / Q000235:genetics*; D005060:Europe; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D012529:Saudi Arabia; D015027:Zebrafish
chemical_list: C586986:CEP120 protein, human; D018797:Cell Cycle Proteins