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ARMC5 encodes an armadillo repeat–containing tumor suppressor implicated in primary macronodular adrenal hyperplasia (PMAH), a rare cause of ACTH-independent Cushing syndrome. Germline inactivating ARMC5 variants follow an autosomal dominant inheritance with incomplete penetrance and predispose to bilateral adrenal macronodularity and cortisol hypersecretion. The gene-disease link is supported by familial segregation, somatic second hits consistent with a two-hit model, and convergent functional data.
A genome-wide linkage and exome sequencing study in a Brazilian kindred identified a heterozygous germline variant c.1094T>C (p.Leu365Pro) segregating in 16 affected relatives ([PMID:24708098]) and somatic ARMC5 defects in adrenal nodules, affirming ARMC5 as a tumor suppressor. Germline deletions of exons 1–5 were reported in a mother–son pair with subclinical PMAH, with an additional missense variant p.Pro347Ser in adrenal lesions ([PMID:26214113]).
A Chinese pedigree exhibited a novel stop-gain c.52C>T (p.Gln18Ter) in 7 of 27 relatives with PMAH, supporting high penetrance in carriers ([PMID:32713866]). In unrelated cohorts, ARMC5 pathogenic variants were found in 24 of 98 index cases of PBMAH, correlating with larger adrenal size, more nodules, and overt Cushing’s syndrome ([PMID:25853793]), while a Japanese series detected ARMC5 defects in 10 of 14 patients, including a recurrent p.Arg619Ter hotspot ([PMID:31555754]).
Functional assays demonstrate that ARMC5 missense mutants fail to induce apoptosis in H295R cells and that variant carriers exhibit higher late-night cortisol and urinary corticosteroids during Liddle’s test ([PMID:24601692], [PMID:25853793]). Immunohistochemistry of PMAH nodules shows increased PCNA and 5HT4R positive cells in ARMC5-mutated tissue, indicating elevated proliferation rates ([PMID:32267363]). ARMC5 expression profiling reveals ubiquitous transcript distribution, with highest levels in adrenal and pituitary glands ([PMID:27568465]).
Biochemical studies show ARMC5 interacts with CUL3 to ubiquitinate and degrade full-length SREBF1/2; ARMC5 loss stabilizes SREBFs, upregulating lipogenic programs and promoting adrenocortical growth ([PMID:35862218]). This molecular mechanism complements the two-hit model and clarifies how ARMC5 deficiency drives cortisol overproduction.
Overall, ARMC5 meets definitive ClinGen criteria: numerous unrelated probands (>100), segregation in multiple families, somatic second hits, and consistent functional concordance. ARMC5 genotyping should be integrated into diagnostic work-ups for bilateral adrenal hyperplasia, guiding early detection and family counseling. Key take-home: ARMC5 germline testing enables precise diagnosis and risk stratification in familial PMAH with ACTH-independent Cushing syndrome.
Gene–Disease AssociationDefinitiveOver 100 unrelated probands with ARMC5 germline variants, multiple familial segregations and somatic second hits, and concordant functional data Genetic EvidenceStrongSegregation in 16 family members ([PMID:24708098]), 98 unrelated index cases with damaging variants ([PMID:25853793]), and two-hit mechanism in adrenal nodules Functional EvidenceModerateIn vitro apoptosis assays and cortisol secretion studies demonstrate loss-of-function effects; molecular assays confirm ARMC5-CUL3 E3 ligase activity |