MEN1 Mutation Genetics: Autosomal Dominant Inheritance Pattern
MEN1 follows an autosomal dominant inheritance pattern, meaning affected individuals carry one mutated MEN1 gene allele and one normal allele (heterozygous state). 1
Inheritance Mechanism
Germline mutations in the MEN1 tumor suppressor gene on chromosome 11q13 are inherited in an autosomal dominant fashion, requiring only one mutated copy to predispose to disease 1
Affected individuals are heterozygous carriers, possessing one pathogenic MEN1 variant and one normal allele 2, 3
Each offspring of an affected parent has a 50% chance of inheriting the mutated allele due to the autosomal dominant pattern 4, 5
Two-Hit Hypothesis for Tumor Development
While individuals inherit one mutated allele, tumor formation requires a second event:
The MEN1 gene functions as a tumor suppressor, requiring loss of both alleles (two hits) for tumor development 2, 6
The first hit is the inherited germline mutation present in all cells 6
The second hit is a somatic mutation that eliminates the normal allele specifically in endocrine tissue, leading to tumor manifestation 2, 6
Four of five informative MEN1-associated tumors showed deletion of the second MEN1 allele, confirming the tumor suppressor mechanism 2
Clinical Implications
Pathogenic germline MEN1 variants are identified in 80-95% of familial cases and 65-70% of de novo cases 1
Identical twins with the same germline MEN1 mutation can show markedly different phenotypes (one with prolactinoma and early pubertal arrest, the other with normal puberty), demonstrating that the second somatic mutation determines tumor expression and timing 6
Genetic testing identifies heterozygous carriers who require lifelong surveillance, while family members without the mutation can be spared unnecessary screening 3