title: A deleterious mutation in SAMD9 causes normophosphatemic familial tumoral calcinosis.
abstract: Familial tumoral calcinosis (FTC) is a rare autosomal recessive disorder characterized by the progressive deposition of calcified masses in cutaneous and subcutaneous tissues, which results in painful ulcerative lesions and severe skin and bone infections. Two major types of FTC have been recognized: hyperphosphatemic FTC (HFTC) and normophosphatemic FTC (NFTC). HFTC was recently shown to result from mutations in two different genes: GALNT3, which codes for a glycosyltransferase, and FGF23, which codes for a potent phosphaturic protein. To determine the molecular cause of NFTC, we performed homozygosity mapping in five affected families of Jewish Yemenite origin and mapped NFTC to 7q21-7q21.3. Mutation analysis revealed a homozygous mutation in the SAMD9 gene (K1495E), which was found to segregate with the disease in all families and to interfere with the protein expression. Our data suggest that SAMD9 is involved in the regulation of extraosseous calcification, a process of considerable importance in a wide range of diseases as common as atherosclerosis and autoimmune disorders.
authors.affiliation: Department of Dermatology and Laboratory of Molecular Dermatology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Orit
authors.initials: O
authors.lastname: Topaz
authors.forename: Margarita
authors.initials: M
authors.lastname: Indelman
authors.forename: Ilana
authors.initials: I
authors.lastname: Chefetz
authors.forename: Dan
authors.initials: D
authors.lastname: Geiger
authors.forename: Aryeh
authors.initials: A
authors.lastname: Metzker
authors.forename: Yoram
authors.initials: Y
authors.lastname: Altschuler
authors.forename: Mordechai
authors.initials: M
authors.lastname: Choder
authors.forename: Dani
authors.initials: D
authors.lastname: Bercovich
authors.forename: Jouni
authors.initials: J
authors.lastname: Uitto
authors.forename: Reuven
authors.initials: R
authors.lastname: Bergman
authors.forename: Gabriele
authors.initials: G
authors.lastname: Richard
authors.forename: Eli
authors.initials: E
authors.lastname: Sprecher
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002114:Calcinosis / Q000235:genetics* / Q000473:pathology; D002460:Cell Line; D003231:Conjunctivitis / Q000235:genetics; D005190:Family; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005891:Gingivitis / Q000235:genetics / Q000473:pathology; D049452:Green Fluorescent Proteins; D006239:Haplotypes; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins; D008126:Lod Score; D008297:Male; D010375:Pedigree; D011506:Proteins / Q000737:chemistry / Q000235:genetics*; D016415:Sequence Alignment; D012871:Skin Diseases / Q000235:genetics / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D012883:Skin Ulcer / Q000235:genetics / Q000473:pathology; D014162:Transfection
chemical_list: C000717427:FGF23 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C514443:SAMD9 protein, human; D049452:Green Fluorescent Proteins; D000089703:Fibroblast Growth Factor-23