title: Novel POC1A mutation in primordial dwarfism reveals new insights for centriole biogenesis.
abstract: POC1A encodes a WD repeat protein localizing to centrioles and spindle poles and is associated with short stature, onychodysplasia, facial dysmorphism and hypotrichosis (SOFT) syndrome. These main features are related to the defect in cell proliferation of chondrocytes in growth plate. In the current study, we aimed at identifying the molecular basis of two patients with primordial dwarfism (PD) in a single family through utilization of whole-exome sequencing. A novel homozygous p.T120A missense mutation was detected in POC1A in both patients, a known causative gene of SOFT syndrome, and confirmed using Sanger sequencing. To test the pathogenicity of the detected mutation, primary fibroblast cultures obtained from the patients and a control individual were used. For evaluating the global gene expression profile of cells carrying p.T120A mutation in POC1A, we performed the gene expression array and compared their expression profiles to those of control fibroblast cells. The gene expression array analysis showed that 4800 transcript probes were significantly deregulated in cells with p.T120A mutation in comparison to the control. GO term association results showed that deregulated genes are mostly involved in the extracellular matrix and cytoskeleton. Furthermore, the p.T120A missense mutation in POC1A caused the formation of abnormal mitotic spindle structure, including supernumerary centrosomes, and changes in POC1A were accompanied by alterations in another centrosome-associated WD repeat protein p80-katanin. As a result, we identified a novel mutation in POC1A of patients with PD and showed that this mutation causes the formation of multiple numbers of centrioles and multipolar spindles with abnormal chromosome arrangement.
authors.affiliation: Department of Medical Genetics, Istanbul University, Cerrahpasa Medical School, Istanbul, Turkey.
authors.forename: Asuman
authors.initials: A
authors.lastname: Koparir
authors.affiliation: Molecular Biology and Genetics Department, Erzurum Technical University, Erzurum, Turkey.
authors.forename: Omer F
authors.initials: OF
authors.lastname: Karatas
authors.affiliation: Advanced Genomics and Bioinformatics Research Center (IGBAM), BİLGEM, TUBITAK, Kocaeli, Turkey.
authors.forename: Betul
authors.initials: B
authors.lastname: Yuceturk
authors.affiliation: Genetic Engineering and Biotechnology Institute, TUBITAK Marmara Research Center, Kocaeli, Turkey.
authors.forename: Bayram
authors.initials: B
authors.lastname: Yuksel
authors.affiliation: Advanced Genomics and Bioinformatics Research Center (IGBAM), BİLGEM, TUBITAK, Kocaeli, Turkey.
authors.forename: Ali O
authors.initials: AO
authors.lastname: Bayrak
authors.affiliation: Advanced Genomics and Bioinformatics Research Center (IGBAM), BİLGEM, TUBITAK, Kocaeli, Turkey.
authors.forename: Omer F
authors.initials: OF
authors.lastname: Gerdan
authors.affiliation: Advanced Genomics and Bioinformatics Research Center (IGBAM), BİLGEM, TUBITAK, Kocaeli, Turkey.
authors.forename: Mahmut S
authors.initials: MS
authors.lastname: Sagiroglu
authors.affiliation: Department of Medical Genetics, Kanuni Sultan Suleyman Training and Research Hospital, 34303 Istanbul, Turkey.
authors.forename: Alper
authors.initials: A
authors.lastname: Gezdirici
authors.affiliation: Department of Molecular Biology and Genetics, Istanbul Technical University, Istanbul, Turkey.
authors.forename: Koray
authors.initials: K
authors.lastname: Kirimtay
authors.affiliation: Department of Molecular Biology and Genetics, Istanbul Technical University, Istanbul, Turkey.
authors.forename: Ece
authors.initials: E
authors.lastname: Selcuk
authors.affiliation: Department of Molecular Biology and Genetics, Istanbul Technical University, Istanbul, Turkey.
authors.forename: Arzu
authors.initials: A
authors.lastname: Karabay
authors.affiliation: Department of Medicine and Dan L Duncan Cancer Center, Division of Biostatistics and.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Creighton
authors.affiliation: Department of Molecular Biology and Genetics, Biruni University, Topkapi, Istanbul, Turkey.
authors.forename: Adnan
authors.initials: A
authors.lastname: Yuksel
authors.affiliation: Department of Medical Genetics, Istanbul University, Cerrahpasa Medical School, Istanbul, Turkey, Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA and Department of Molecular Biology and Genetics, Biruni University, Topkapi, Istanbul, Turkey mozen@bcm.edu.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Ozen
mesh_terms: D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D002502:Centrioles / Q000378:metabolism*; D002648:Child; D002869:Chromosome Aberrations; D003598:Cytoskeletal Proteins; D004392:Dwarfism / Q000235:genetics*; D059472:Exome; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010704:Phorbols; D011506:Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods*; D012867:Skin / Q000166:cytology
chemical_list: D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; C575745:POC1A protein, human; D010704:Phorbols; D011506:Proteins; C470237:pedilstatin