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.
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We are grateful to the family members for their enthusiastic, continuous, and generous participation in our study. We thank Vered Friedman, for her help with nucleic acid analysis, and Israel Vlodawski, Dan Kassel, Ami Aronheim, and Mia Horovitz, for providing us with reagents and for stimulating discussions. This study was supported in part by grants from the Israel Science Foundation; the Rappaport Institute for Research in the Medical Sciences, Technion; and National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin grant R01 AR052627.