title: Mutations in KIAA0753 cause Joubert syndrome associated with growth hormone deficiency.
abstract: Joubert syndrome and related disorders (JSRD) are a heterogeneous group of ciliopathies defined based on the mid-hindbrain abnormalities that result in the characteristic "molar tooth sign" on brain imaging. The core clinical findings of JSRD are hypotonia, developmental delay, abnormal eye movements and breathing abnormalities. To date, more than 30 JSRD genes that encode proteins important for structure and/or function of cilia have been identified. Here, we present 2 siblings with Joubert syndrome associated with growth hormone deficiency. Whole exome sequencing of the family identified compound heterozygous mutations in KIAA0753, i.e., a missense mutation (p.Arg257Gly) and an intronic mutation (c.2359-1G>C). The intronic mutation alters normal splicing by activating a cryptic acceptor splice site in exon 16. The novel acceptor site skips nine nucleotides, deleting three amino acids from the protein coding frame. KIAA0753 (OFIP) is a centrosome and pericentriolar satellite protein, previously not known to cause Joubert syndrome. We present comprehensive clinical descriptions of the Joubert syndrome patients as well as the cellular phenotype of defective ciliogenesis in the patients' fibroblasts.
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Joshi
authors.initials: J
authors.lastname: Stephen
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.|Division of Medical Genomics, Inova Translational Medicine Institute, Falls Church, VA, USA.
authors.forename: Thierry
authors.initials: T
authors.lastname: Vilboux
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Luhe
authors.initials: L
authors.lastname: Mian
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Chulaluck
authors.initials: C
authors.lastname: Kuptanon
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Courtney M
authors.initials: CM
authors.lastname: Sinclair
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Deniz
authors.initials: D
authors.lastname: Yildirimli
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Maynard
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Joy
authors.initials: J
authors.lastname: Bryant
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Roxanne
authors.initials: R
authors.lastname: Fischer
authors.affiliation: NIH Intramural Sequencing Center (NISC), National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Meghana
authors.initials: M
authors.lastname: Vemulapalli
authors.affiliation: NIH Intramural Sequencing Center (NISC), National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Mullikin
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Marjan
authors.initials: M
authors.lastname: Huizing
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.|NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, USA.|Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. malicdanm@mail.nih.gov.|NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, Bethesda, MD, USA. malicdanm@mail.nih.gov.|Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. malicdanm@mail.nih.gov.
authors.forename: May Christine V
authors.initials: MCV
authors.lastname: Malicdan
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. mgaygun@mail.nih.gov.|Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. mgaygun@mail.nih.gov.|Department of Pediatrics and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. mgaygun@mail.nih.gov.
authors.forename: Meral
authors.initials: M
authors.lastname: Gunay-Aygun
mesh_terms: D000015:Abnormalities, Multiple / Q000000981:diagnostic imaging / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D002531:Cerebellum / Q000002:abnormalities* / Q000000981:diagnostic imaging; D002648:Child; D005124:Eye Abnormalities / Q000000981:diagnostic imaging / Q000235:genetics*; D005260:Female; D013006:Growth Hormone / Q000172:deficiency*; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000000981:diagnostic imaging / Q000235:genetics*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009154:Mutation; D012160:Retina / Q000002:abnormalities* / Q000000981:diagnostic imaging; D017386:Sequence Homology, Amino Acid
chemical_list: C000612074:KIAA0753 protein, human; D008869:Microtubule-Associated Proteins; D013006:Growth Hormone