Alt. symbols: C7orf5 | KIAA2004 | FLJ20073

Approved name: sterile alpha motif domain containing 9
Alt. names: chromosome 7 open reading frame 5

Location: 7q21.2: 93099513 - 93118023 (-)
Gene type: protein_coding, 3 transcripts.

Scores: LoFtool: 0.991000 | pLI: 0.00000000 | LOEUF: 1.243

HGNC: 1348

NCBI: 54809, RefSeq: NG_023419.1

Ensembl: ENSG00000205413.8

LRG_ | Status: none

OMIM: 610456

Expression | ProteinAtlas

Sterile alpha motif domain-containing protein 9 (SAMD9) is putatively involved in endosomal fusion and may affect signaling that depends on endosomal trafficking. It broadly expressed, most prominently in the esophagus, appendix, spleen, lymph nodes and colon (PMID: 24309898). TNFa exposure increases SAMD9 expression (PMID): 18094730). Overexpression is reported to lead to apoptosis in some malignancies, while reduced expression appears to enhances proliferation (PMID: 17407603), suggesting a role in tumor suppression. In vitro, miRNA-mediated downregulation of SAMD9 increased the resistance of NSCLC-cells to cisplatin (PMID: 26893673). Its N-terminus is able to bind myxoma virus protein M062 (PMID: 28157624).

Biallelic missense, nonsense, and frameshift mutations in SAMD9 are associated with normophosphatemic familial tumoral carcinosis (NFTC) [MIM:610455], a rare autosomal recessive disorder found predominantly in families of Jewish-Yemmenite origin. NFTC is characterized by massive periarticular, and seldom visceral, deposition of calcified tumors at sites of repetitive trauma, along with abnormal skin and gingival inflammation. Unlike hyperphosphatemic FTC (HFTC) associated with mutations in GALNT 3, FGF23 or KL, NFTC shows no pathologically increased renal absorption of phosphate and routine laboratory tests, including calcium, phosphate, vitamin D3 metabolites, and parathyroid-hormone levels are normal. Whereas HFTC models metastatic calcinosis, which refers to deposition of calcified materials due to abnormal calcium phosphate metabolism, as seen in chronic renal failure, NFTC is more reminiscent of acquired dystrophic calcinosis, in which tissue calcification occurs as a consequence of tissue injury/inflammation, as observed in many unrelated conditions such as vascular disease, cancer, and autoimmune disorders (PMID: 16960814). The conspicuous inflammatory malformations seen in NFTC but absent from HFTC suggest that the SAMD9 protein may be involved in physiologic responses to tissue injury downstream of TNF-alpha signaling. More recently, monoallelic missense gain-of-function mutations in SAMD9 have been associated with autosomal dominant MIRAGE syndrome [MIM:617053] and the related monosomy 7 myelodysplasia and leukemia syndrome 2 (M7MLS2) [MIM: 619041]. MIRAGE syndrome is a form of syndromic adrenal hypoplasia, characterized by dysmorphic features, myelodysplasia with monosomy 7, infections and immunodeficiency, prenatal and postnatal growth restriction, adrenal hypoplasia, congenital genitourinary anomalies, and enteropathy with most affected individuals passing away in early childhood. Additional features that have been reported include hearing loss, renal anomalies, brain MRI abnormalities, and dysautonomia. M7MLS2 is thought to be a milder condition on the same spectrum, often with incomplete penetrance due to somatic reversion. Buonocore et al. (2017) first noted a preponderance of mutations altering Arg residues across various domains of the protein. The immunophenotypes of MIRAGE patients remains poorly understood. Most individuals develop recurrent bacterial infections from early infancy including pneumonia, urinary tract infection, gastroenteritis, meningitis, otitis media, dermatitis, subcutaneous abscess, and sepsis. The most common organisms associated with these infections are enteric pathogens such as Klebsiella and Enterococcus. Individuals with severe immunodeficiency are likely also at increased susceptibility to viral and fungal infections, though the exact etiology of the increased susceptibility to infections remains unknown. Inadequate vaccine responses, hypogammaglobulinemia, lymphopenia (though usually without significant abnormalities on lymphocyte subsets), and thymic hypoplasia have been reported (PMID: 27182967, 29266745, 29365320). More recently, Formankova et al. (2019) described a novel SAMD9 variant (c.2471 G>A, p.R824Q) in a boy with severe early CMV infection, recurrent infections, periodic recurrent fevers with elevated inflammatory markers, prominent gastrointestinal disease and immunodeficiency featuring qualitative and quantitative lymphocyte defects, but no sign of the adrenal insufficiency typ [Load More]