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The sterile α motif domain–containing protein 9 (SAMD9) is a TNF-alpha–responsive protein involved in regulating cellular responses to stress. Biallelic loss-of-function variants in SAMD9 underlie the rare autosomal recessive Normophosphatemic familial tumoral calcinosis (NFTC), characterized by pathological calcium deposition in skin and mucosae, severe pain, and life-threatening infections. Identification of SAMD9 as the causal gene for NFTC has provided crucial insights into the link between inflammatory signaling and extra-osseous calcification.
Initial genetic analyses in five unrelated Jewish-Yemenite families revealed a homozygous missense variant c.4483A>G (p.Lys1495Glu) resulting in SAMD9 protein degradation and NFTC presentation ([PMID:18094730]). In a subsequent kindred, affected siblings were compound heterozygous for p.Lys1495Glu and c.1030C>T (p.Arg344Ter) ([PMID:18094730]). Unaffected relatives were heterozygous carriers, confirming autosomal recessive inheritance of NFTC due to biallelic SAMD9 disruption.
Across these six families, at least seven probands have been described with consistent clinical presentation. The variant spectrum is limited to destabilizing missense changes (p.Lys1495Glu) and truncating alleles (p.Arg344Ter), with no other variant classes reported to date. Screening of over 700 control chromosomes identified these alleles exclusively in Jewish-Yemenite individuals, suggesting a founder effect and population specificity.
Functional assays demonstrated that hyperosmotic shock robustly upregulated SAMD9 transcription, whereas oxidative and heat stresses did not. Crucially, TNF-alpha treatment induced a dose-dependent, p38 MAPK–dependent increase in SAMD9 expression in endothelial cells, directly linking the TNF-alpha signaling pathway to regulation of calcification in NFTC ([PMID:18094730]).
Loss-of-function of SAMD9 due to protein degradation or truncation likely impairs its anti-inflammatory and calcification-inhibitory functions, leading to uncontrolled calcium deposition in skin and mucosa. Concordant genotype–phenotype correlations across multiple families and cellular assays define a consistent biological mechanism for NFTC.
Genetic and functional evidence support a Strong clinical validity for SAMD9 in NFTC. Diagnostic testing for biallelic SAMD9 variants should be prioritized in patients with normophosphatemic tumoral calcinosis, especially of Jewish-Yemenite descent, and carrier screening may inform community risk assessment. Key Take-home: Loss-of-function SAMD9 variants cause NFTC via impaired inflammatory calcification regulation, and targeted SAMD9 analysis has immediate clinical utility.
Gene–Disease AssociationStrongBiallelic SAMD9 variants identified in six independent families, autosomal recessive segregation, and concordant functional data ([PMID:18094730]) Genetic EvidenceStrong≥7 probands from six unrelated Jewish-Yemenite families with missense and truncating SAMD9 variants, confirmed recessive segregation ([PMID:18094730]) Functional EvidenceModerateOsmotic shock and TNF-alpha–dependent induction assays demonstrate SAMD9’s role in inflammatory calcification regulation ([PMID:18094730]) |