Our objective was to functionally characterize a panel of 16 menin missense mutants, including W423R and S443Y identified in new MEN1 families, with respect to protein stability, targeting to the proteasome and restoration of expression by proteasome inhibitors and expression and function by small interfering RNA technology.
The different ages of disease presentation and the heterogeneity of symptoms among carriers of the Trp471Stop mutation, which would lead to the synthesis of a truncated non-functional protein, suggest that clinical heterogeneity is a characteristic of MEN1 independent of the type of mutation.
We demonstrated that members of a three-generation MEN1 kindred are heterozygous for a donor splice site mutation at the beginning of intron 3 (IVS3 + 1G→A).
Some missense and in-frame deletion mutants (G28A, R171W, T197I, E255K, E274A, Y353del and E366D) associated with FIHP or ASPT were almost as stable as or only slightly less stable than wild-type menin, while others were as unstable as those associated with typical MEN1.
Our finding of p.Arg16His AIP in one of the 95 controls and its co-occurrence with MEN1 in a patient suggests that it is more likely that this variant is a rare polymorphism, unrelated to MEN1 pathogenesis.