title: Short stature, onychodysplasia, facial dysmorphism, and hypotrichosis syndrome is caused by a POC1A mutation.
abstract: Disproportionate short stature refers to a heterogeneous group of hereditary disorders that are classified according to their mode of inheritance, clinical skeletal and nonskeletal manifestations, and radiological characteristics. In the present study, we report on an autosomal-recessive osteocutaneous disorder that we termed SOFT (short stature, onychodysplasia, facial dysmorphism, and hypotrichosis) syndrome. We employed homozygosity mapping to locate the disease-causing mutation to region 3p21.1-3p21.31. Using whole-exome-sequencing analysis complemented with Sanger direct sequencing of poorly covered regions, we identified a homozygous point mutation (c.512T>C [p.Leu171Pro]) in POC1A (centriolar protein homolog A). This mutation was found to cosegregate with the disease phenotype in two families. The p.Leu171Pro substitution affects a highly conserved amino acid residue and is predicted to interfere with protein function. Poc1, a POC1A ortholog, was previously found to have a role in centrosome stability in unicellular organisms. Accordingly, although centrosome structure was preserved, the number of centrosomes and their distribution were abnormal in affected cells. In addition, the Golgi apparatus presented a dispersed morphology, cholera-toxin trafficking from the plasma membrane to the Golgi was aberrant, and large vesicles accumulated in the cytosol. Collectively, our data underscore the importance of POC1A for proper bone, hair, and nail formation and highlight the importance of normal centrosomes in Golgi assembly and trafficking from the plasma membrane to the Golgi apparatus.
authors: Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv 642395, Israel.
authors: Ofer
authors: O
authors: Sarig
authors: Sagi
authors: S
authors: Nahum
authors: Debora
authors: D
authors: Rapaport
authors: Akemi
authors: A
authors: Ishida-Yamamoto
authors: Dana
authors: D
authors: Fuchs-Telem
authors: Li
authors: L
authors: Qiaoli
authors: Ksenya
authors: K
authors: Cohen-Katsenelson
authors: Ronen
authors: R
authors: Spiegel
authors: Janna
authors: J
authors: Nousbeck
authors: Shirli
authors: S
authors: Israeli
authors: Zvi-Uri
authors: ZU
authors: Borochowitz
authors: Gilly
authors: G
authors: Padalon-Brauch
authors: Jouni
authors: J
authors: Uitto
authors: Mia
authors: M
authors: Horowitz
authors: Stavit
authors: S
authors: Shalev
authors: Eli
authors: E
authors: Sprecher
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000595:Amino Acid Sequence; D001483:Base Sequence; D018797:Cell Cycle Proteins; D002874:Chromosome Mapping; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D003598:Cytoskeletal Proteins; D059472:Exome / Q000235:genetics; D005260:Female; D006056:Golgi Apparatus / Q000473:pathology; D006801:Humans; D007039:Hypotrichosis / Q000235:genetics*; D007211:Indoles; D008297:Male; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics; D012150:Polymorphism, Restriction Fragment Length / Q000235:genetics; D021381:Protein Transport / Q000235:genetics; D011506:Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D007211:Indoles; C575745:POC1A protein, human; D011506:Proteins; C007293:DAPI