MEN1 – Multiple Endocrine Neoplasia Type 1

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome characterized by parathyroid hyperplasia/adenomas, pituitary prolactin-cell adenomas and enteropancreatic neuroendocrine tumours with age-related penetrance reaching >98% by 40 years. Germline variants in MEN1 (HGNC:7010) confer high lifetime risk for multi-gland endocrine neoplasia and guide early surveillance and intervention.

Extensive genetic studies in 63 unrelated kindreds (195 affected members) established MEN1 as a tumour suppressor gene, with heterozygous germline mutations in 76% of familial probands and 8/11 sporadic cases ([PMID:9463336]). Multi-generational segregation of the in-frame missense variant c.134A>G (p.Glu45Gly) in seven affected relatives supports pathogenicity and utility for predictive testing ([PMID:10395230]). Over 114 distinct germline alterations—including truncating, splice-site and missense mutations—are distributed throughout MEN1 without clear genotype–phenotype correlation ([PMID:12112656]). Loss of the wild-type allele in tumours confirms a two-hit mechanism of menin inactivation.

Germline c.134A>G (p.Glu45Gly) exemplifies the variant spectrum: this missense substitution segregates with hyperparathyroidism and thymic carcinoid in a large pedigree and is absent in 50 controls ([PMID:10395230]). The MEN1 mutational landscape also includes recurrent founder and de novo mutations at hotspots (codons 83–84, 118–119, 418, 516), accounting for ~36% of mutations and facilitating targeted screening ([PMID:12050235]).

Functional assays demonstrate that menin directly binds the AP1 transcription factor JunD to repress JunD-activated transcription ([PMID:9989505]) and recruits an mSin3A–histone deacetylase complex for transcriptional silencing ([PMID:14559791]). Rodent and Drosophila orthologs of menin mirror human function, and Men1 knockout mice exhibit embryonic lethality and endocrine tumours, underscoring a conserved tumour suppressor role ([PMID:10818209]; [PMID:11536432]). Allelic loss of wild-type MEN1 in parathyroid adenomas further validates menin’s in vivo tumour suppressor activity ([PMID:10580746]).

Conflicting evidence arises from phenocopies: familial hypocalciuric hypercalcemia and hyperparathyroidism-jaw tumour syndrome, due to CASR and CDC73 mutations, can mimic MEN1 features and account for ~5% of clinically suspected families ([PMID:19953642]). Sporadic pituitary adenomas rarely harbour MEN1 mutations and often upregulate menin expression, indicating distinct oncogenic pathways ([PMID:12030908]).

In summary, MEN1 is definitively associated with multiple endocrine neoplasia type 1 through robust genetic, segregation and functional evidence. MEN1 germline testing identifies at-risk carriers for tailored surveillance, guides surgical and medical management, and underpins genetic counselling. Early detection of MEN1 mutations enables preclinical intervention and improved outcomes.

References

• American Journal of Human Genetics • 1998 • Characterization of mutations in patients with multiple endocrine neoplasia type 1 PMID:9463336
• Endocrine Journal • 1998 • A family of MEN1 with a novel germline missense mutation and benign polymorphisms PMID:10395230
• Human Mutation • 2002 • Germline mutation profile of MEN1 in multiple endocrine neoplasia type 1 PMID:12112656
• Cell • 1999 • Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription PMID:9989505
• Cancer Research • 2003 • Menin, a tumor suppressor, represses JunD-mediated transcriptional activity by association with an mSin3A-histone deacetylase complex PMID:14559791
• Biochimica et Biophysica Acta • 1999 • Primary structure, gene expression and chromosomal mapping of rodent homologs of the MEN1 tumor suppressor gene PMID:10524203
• Genesis • 2001 • Bidirectional transcriptional activity of PGK-neomycin and unexpected embryonic lethality in heterozygote chimeric knockout mice PMID:11536432
• Endocrine Journal • 1999 • Loss of wild-type MEN1 gene expression in multiple endocrine neoplasia type 1-associated parathyroid adenoma PMID:10580746
• Human Mutation • 2010 • Diagnostic challenges due to phenocopies: lessons from Multiple Endocrine Neoplasia type1 (MEN1) PMID:19953642
• Clinical Endocrinology • 2002 • Increased menin expression in sporadic pituitary adenomas PMID:12030908

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