Abstract
Despite its identification in 1997, the functions of the MEN1 gene—the main gene underlying multiple endocrine neoplasia type 1 syndrome—are not yet fully understood. In addition, unlike the RET—MEN2 causative gene—no hot-spot mutational areas or genotype–phenotype correlations have been identified. More than 1,300 MEN1 gene mutations have been reported and are mostly "private” (family specific). Even when mutations are shared at an intra- or inter-familial level, the spectrum of clinical presentation is highly variable, even in identical twins. Despite these inherent limitations for genetic counseling, identifying MEN1 mutations in individual carriers offers them the opportunity to have lifelong clinical surveillance schemes aimed at revealing MEN1-associated tumors and lesions, dictates the timing and scope of surgical procedures, and facilitates specific mutation analysis of relatives to define presymptomatic carriers.
Highlights
Multiple endocrine neoplasia type 1 syndrome (MEN1, MIM*131100) is an autosomal dominant disorder in which varying combinations of either endocrine or non-endocrine tumors may present extremely varied phenotypic clinical patterns
Linkage analysis approach: it cannot be considered totally obsolete In the past, before cloning the MEN1 gene in 199720,21, linkage analysis was the only clinically useful approach for genetic diagnosis; it uses highly polymorphic DNA markers located upstream and downstream of 11q13, the chromosomal region to which the MEN1 gene was mapped[17,18,19]
Since some of these DNA markers show no recombination with the MEN1 gene (i.e. PYGM, D11S463, and D11S427), an accuracy of up to 99.5% could be reached in the test for carriers, with incorrect results due to meiotic crossing over being omitted[5,21]
Summary
Multiple endocrine neoplasia type 1 syndrome (MEN1, MIM*131100) is an autosomal dominant disorder in which varying combinations of either endocrine or non-endocrine tumors may present extremely varied phenotypic clinical patterns. The results suggest that MEN1 tumorigenesis may be under “negative feedback loop” control between miR-24-1 and menin, mimicking the Knudson’s second hit and possibly buffering the effect of the stochastic factors hypothesized to contribute to the onset and progression of MEN1 disease[79] If such findings are confirmed by other studies in other MEN1 tumors from subjects with the same or different MEN1 gene mutations, they could suggest the existence of an alternative pathway to MEN1 tumorigenesis and, probably, to the ‘Knudson’s two-hits dogma or, maybe, an alternative MEN1 tumorigenesis for specific MEN1-affected endocrine and non-endocrine tissues. Grant information The author(s) declared that no grants were involved in supporting this work
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