Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Gene expression profiling of fibroblasts harboring POC1A mutation

ABSTRACT: POC1A encodes a WD repeat protein localizing to centrioles and spindle poles and associated with Short stature, onychodysplasia, facial dysmorphism and hypotrichosis (SOFT) syndrome (OMIM #614813). In our study, we reported on two patients with primordial dwarfism (PD) from the same family. We utilized Whole Exome Sequencing (WES) in the patients to screen all PD related genes and to define putative novel candidate genes. A novel homozygous p.T120A missense mutation was detected in POC1A, a known causative gene of SOFT syndrome, and confirmed using Sanger sequencing. To confirm the pathogenicity of the detected mutation, primary fibroblast cultures obtained from the patients and a control individual were used. Gene expression profiles of the fibroblast cultures were taken. We performed gene expression arrays on fibroblasts cultured from patients with SOFT syndrome and POC1A mutation and compared their expression profiles to that of control fibroblast cells.

ORGANISM(S): Homo sapiens

SUBMITTER: Chad Creighton

PROVIDER: E-GEOD-66314 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Novel POC1A mutation in primordial dwarfism reveals new insights for centriole biogenesis.

Koparir Asuman A Karatas Omer F OF Yuceturk Betul B Yuksel Bayram B Bayrak Ali O AO Gerdan Omer F OF Sagiroglu Mahmut S MS Gezdirici Alper A Kirimtay Koray K Selcuk Ece E Karabay Arzu A Creighton Chad J CJ Yuksel Adnan A Ozen Mustafa M

Human molecular genetics 20150710 19

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 ...[more]

PMID: 26162852

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Project description:A disintegrin-like and metalloprotease domain with thrombospondin type 1 repeats-like 2 (ADAMTSL2) is a matricellular protein that interacts with latent TGF-b binding protein 1 and fibrillin-1. ADAMTSL2 mutations cause an autosomal recessive connective tissue disorder named geleophysic dysplasia 1 (GPHYSD1, OMIM #231050), which is characterized by short stature, small hands and feet, and cardiac defects. ADAMTSL2 contains seven thrombospondin type-1 repeats (TSRs), six of which contain the consensus sequence for serine or threonine glycosylation by protein O-fucosyltransferase 2 (POFUT2). O-fucose modified TSRs are subsequently elongated to a Glucose1-3Fucose (GlcFuc) disaccharide by b3-glucosyltransferase (B3GLCT). B3GLCT mutations cause Peters Plus Syndrome (PTRPLS, OMIM #261540), which is characterized by skeletal defects similar to those of GPHYSD1. Several ADAMTSL2 TSRs have consensus sequences for C-mannosylation, and one TSR contains a sequon for N-glycosylation that overlaps with an O-fucosylation site. Six reported GPHYSD1 mutations occur within the TSRs and two lie near O-fucosylation sites. To investigate the effects of TSR glycosylation on ADAMTSL2 function, we used mass spectrometry to identify glycan modifications at the predicted consensus sequences. We found that most TSRs were modified with the GlcFuc disaccharide at high stoichiometry at O-fucosylation sites and variable mannose stoichiometry at C-mannosylation sites. Loss of ADAMTSL2 secretion in POFUT2 knockout but not in B3GLCT knockout cells suggested that impaired ADAMTSL2 secretion is not responsible for skeletal defects in PTRPLS patients lacking B3GLCT. In contrast, secretion of mouse ADAMTSL2 carrying GPHYSD1 mutations (S641L in TSR3 and G817R in TSR6) was significantly reduced in HEK293T cells. Moreover, S641L eliminated O-fucosylation of TSR3. Combined these results provide strong evidence that developmental abnormalities in GPHYSD1 patients with this mutation are caused by loss of O-fucosylation on TSR3 and impaired ADAMTSL2 secretion.

Dataset Information

Gene expression profiling of fibroblasts harboring POC1A mutation

Publications

Novel POC1A mutation in primordial dwarfism reveals new insights for centriole biogenesis.

Similar Datasets

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