ARMC5 – Cushing syndrome

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing syndrome characterized by bilateral macronodular adrenal nodules and hypercortisolism. ARMC5 was identified as the major tumor suppressor gene mutated in familial and sporadic PBMAH, with heterozygous germline variants and somatic second hits driving adrenal tumorigenesis (PMID:24708098).

In a Brazilian kindred of 47 individuals, a heterozygous missense variant c.1094T>C (p.Leu365Pro) segregated with disease in 16 affected relatives, each adrenal nodule harboring a distinct somatic ARMC5 alteration, supporting the two-hit model for tumor suppressor inactivation (PMID:24708098). Independent sequencing of 98 unrelated PBMAH index cases identified ARMC5-damaging variants in 24 (26%), with mutation carriers exhibiting more severe hypercortisolism and larger adrenal masses compared to wild-type patients (PMID:25853793).

Case series in French-Canadian and Chinese cohorts documented recurrent truncating ARMC5 frameshift variants such as c.327dup (p.Ala110ArgfsTer9) in nine carriers and c.52C>T (p.Gln18Ter) in seven carriers with overt or subclinical Cushing syndrome, with somatic second hits also found in adrenal and meningioma tissues (PMID:26604299; PMID:32713866; PMID:25279498).

The ARMC5 variant spectrum includes missense (e.g., c.1094T>C (p.Leu365Pro)), nonsense (e.g., c.517C>T (p.Arg173Ter)), frameshift and splice-site changes. Analysis of 20 adrenal nodules from one patient revealed 16 distinct somatic inactivating events in addition to a germline p.Trp476Ter defect, confirming extensive allelic heterogeneity (16/20 nodules; PMID:26162405).

Functional studies demonstrate that ARMC5 missense mutants fail to induce apoptosis in H295R and HeLa cells, unlike wild-type ARMC5, and that ARMC5 serves as a substrate adaptor for CUL3 E3 ligase to ubiquitinate full-length SREBF proteins, linking ARMC5 loss to aberrant steroidogenic signaling in adrenocortical cells (PMID:25853793; PMID:35862218). Ubiquitous ARMC5 expression, with highest levels in adrenal and pituitary tissues, suggests potential roles beyond the adrenal cortex (PMID:27568465).

No studies have significantly disputed ARMC5’s role in PBMAH; cases without ARMC5 mutations implicate alternative drivers such as KDM1A. Current evidence exceeds ClinGen scoring caps for genetic and functional data.

Key take-home: ARMC5 genetic testing should be implemented in patients with bilateral adrenal nodules and Cushing syndrome to enable early diagnosis, targeted surveillance, and familial risk assessment.

References

• The Journal of Clinical Endocrinology and Metabolism • 2014 • Inherited autosomal dominant mutations in the ARMC5 gene are a frequent cause of PMAH PMID:24708098
• The Journal of Clinical Endocrinology and Metabolism • 2015 • ARMC5 Mutations in a Large Cohort of Primary Macronodular Adrenal Hyperplasia: Clinical and Functional Consequences. PMID:25853793
• The Journal of Clinical Endocrinology and Metabolism • 2014 • Macronodular adrenal hyperplasia due to mutations in an armadillo repeat containing 5 (ARMC5) gene: a clinical and genetic investigation. PMID:24601692
• Journal of the Endocrine Society • 2019 • ARMC5 Alterations in Primary Macronodular Adrenal Hyperplasia (PMAH) and the Clinical State of Variant Carriers. PMID:31555754
• European Journal of Endocrinology • 2016 • ARMC5 mutations in a large French-Canadian family with cortisol-secreting β-adrenergic/vasopressin responsive bilateral macronodular adrenal hyperplasia PMID:26604299
• Endocrine Journal • 2020 • Primary macronodular adrenal hyperplasia (PMAH) can be generated by a new ARMC5 germline variant (c.52C>T (p.Gln18X)). PMID:32713866
• European Journal of Endocrinology • 2015 • The ARMC5 gene shows extensive genetic variance in primary macronodular adrenocortical hyperplasia. PMID:26162405
• Molecular and Cellular Endocrinology • 2017 • Analysis of ARMC5 expression in human tissues. PMID:27568465
• JCI Insight • 2022 • ARMC5-CUL3 E3 ligase targets full-length SREBF in adrenocortical tumors. PMID:35862218

Evidence Based Scoring (AI generated)