Normophosphatemic familial tumoral calcinosis is caused by deleterious mutations in SAMD9, encoding a TNF-α responsive protein

Ilana Chefetz, Danny Ben Amitai, Sarah Browning, Karl Skorecki, Noam Adir, Mark G. Thomas, Larissa Kogleck, Orit Topaz, Margarita Indelman, Jouni Uitto, Gabriele Richard, Neil Bradman, Eli Sprecher

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56 Scopus citations


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-α (TNF-α), 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-α caused a dose-related, p38-dependant increase in SAMD9 expression. These data link NFTC and SAMD9 to the TNF-α signaling pathway, suggesting a role for this system in the regulation of extra-osseous calcification.

Original languageEnglish (US)
Pages (from-to)1423-1429
Number of pages7
JournalJournal of Investigative Dermatology
Issue number6
StatePublished - Jun 2008
Externally publishedYes

Bibliographical note

Funding Information:
We are grateful to the family members for their enthusiastic and generous participation in our study. We wish to thank Vered Friedman and Rita Fuhrer-Mor for their help with nucleic acid analysis, Uri Seligshon for providing DNA samples, and Ariel Miller and Tamar Paperna for the gift of the EaHy cells. This study was supported in part by grants provided by Israel Science Foundation, the Rappaport Institute for Research in the Medical Sciences, NIH/NIAMS Grant R01 AR052627 and the Veronique Simone and Barry and Carole Rose Funds of the Canadian Technion Society.

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