Normophosphatemic Familial Tumoral Calcinosis Is Caused by Deleterious Mutations in SAMD9, Encoding a TNF-α Responsive Protein

Abstract

Normophosphatemic familial tumoral calcinosis (NFTC) is an autosomal recessive disorder characterized by calcium deposition in skin and mucosae and associated with unremitting pain and life-threatening skin infections. A homozygous missense mutation (p.K1495E), resulting in SAMD9 protein degradation, was recently shown to cause NFTC in five families of Jewish-Yemenite origin. In this study, we evaluated another Jewish-Yemenite NFTC kindred. All patients were compound heterozygous for two mutations in SAMD9: K1495E and a previously unreported nonsense mutation, R344X, predicted to result in a markedly truncated molecule. Screening of unaffected population-matched controls revealed heterozygosity for K1495E and R344X only in individuals of Jewish-Yemenite ancestry, but not in more than 700 control samples of other origins, including 93 non-Jewish Yemenite. These data may be suggestive of positive selection, considering the rarity of NFTC and the small size of the Jewish-Yemenite population; alternatively, they may reflect genetic drift or the effect of a population-specific modifier trait. Calcifications in NFTC generally develop over areas subjected to repeated trauma and are associated with marked inflammatory manifestations, indicating that SAMD9 may play a role in the inflammatory response to tissue injury. We therefore assessed the effect of cellular stress and tumor necrosis factor-alpha (TNF-alpha), a potent pro-inflammatory cytokine, on SAMD9 gene expression. Whereas exogenous hydrogen peroxide and heat shock did not affect SAMD9 transcription, osmotic shock was found to markedly upregulate SAMD9 expression. In addition, incubation of endothelial cells with TNF-alpha caused a dose-related, p38-dependant increase in SAMD9 expression. These data link NFTC and SAMD9 to the TNF-alpha signaling pathway, suggesting a role for this system in the regulation of extra-osseous calcification.

Longitudinal system-based analysis of transcriptional responses to type I interferons

“…The general response hub SAMD9L has no known connections to the IFN response but has recently been shown to be downregulated in aggressive fibromatosis (47) and causes normophasphatemic familial tumoral calcinosis (NFTC) through unknown mechanisms (9). Compared with other types of calcinosis, NTFC displays conspicuous inflammatory manifestations (9).…”

“…Compared with other types of calcinosis, NTFC displays conspicuous inflammatory manifestations (9). SAMD9L upregulation may in part explain the limited success of type I IFNs in treating various forms of cancer (65,69).…”

Overexpression of SAMD9 suppresses tumorigenesis and progression during non small cell lung cancer

“…The Sterile Alpha Motif Domaincontaining 9 (SAMD9) gene is located in chromosome 7q21.2 of the human genome, and separated by approximately 12 kb. Tt plays important roles in normophosphatemic familiar tumoral calcinosis (NFTC) [3,4]. SAMD9 has been demonstrated to be associated with aggressive fibromatosis, breast, and colon cancers and it is expressed at a lower level [5].…”

“…However, very few studies focus on the expression and function of SAMD9 in human NSCLC. Human SAMD9 expression can be downregulated by tumor necrosis factor (TNF) [4] or by type I [6] and type II interferons (IFNs) [7], and it is classified as an interferon stimulated gene (ISG). Recently, the human SAMD9 is expressed in normal breast tissues and primary tumor tissues, it was shown to exhibit higher expression levels in normal tissues [5].…”

Bilateral Dystrophic Calcinosis Circumscripta in a Cynomolgus Macaque (Macaca fascicularis)

“…Disorders that may be associated with dystrophic calcification are Ehlers-Danlos syndrome, pseudoxanthoma elasticum, arteriosclerosis obliterans, venous calcifications, crystal deposition disorders, and calcification resulting from neurologic disorders (Black and Kanat 1985). A recently described autosomal recessive disorder in humans is called familial tumoral calcinosis (FTC), particularly a form of the syndrome that is characterized by an absence of metabolic abnormalities, termed normophosphatemic (NFTC; Chefetz et al 2008;Sprecher 2009). NFTC is associated with an absence of functional SAMD9, a putative tumor suppressor and antiinflammatory protein (Chafetz et al 2008).…”