ADDITIONAL CANDIDATE GENES FOR GERMLINE MUTATION IN MEN1-L1KE STATES

Background: Familial index cases of multiple endocrine neoplasia type 1 (MEN1) have a 60-80% prevalence of identifiable germ line MENI mutation. The prevalence is much lower in sporadic index cases (as low as 7% with both parathyroid and pituitary tumor) or in other MEN1like states such as familial isolated hyperparathyroidism (10%) and familial isolated pituitary tumor (below 1 %). Among these patients, some may have an MEN 1 mutation that was not detected by standard screening methods (direct sequencing of coding exons and splice junctions); e.g., large deletions (12 reported so far among approximately 800 distinct MEN 1 mutations) or mutations outside of the regions sequenced. However, some are likely to have mutations in other genets). A rat strain with a recessive MENlike syndrome (MENX) with tumors encompassing MEN1 and MEN2 has a homozygous germ line inactivating mutation in the cyclin-dependent kinase inhibitor (CDKI) p27. Also, two different heterozygous germline p27 mutations have been found in two human index cases with an MEN1like state (termed MEN4 by OMIM) (Pellegata et aI., 2006; Georgitsi et aI., 2007).

Methods: We screened for germ line p27 mutations by PCR and sequencing in 34 index cases with MEN1-like disease (mainly parathyroid and pituitary tumor); each previously negative for MENI mutation.

Results: We did not detect a germ line p27 mutation in any of the 34 index cases (Ozawa et aI., 2007).

Summary/Conclusions: p27 mutation in this MEN1-like state (with mainly parathyroid and pituitary tumor) is rare, likely less than 1 %. A large and diverse number of MEN1like states remain with presumed causative genes unidentified. However, evidence from endocrine tumors observed in various combinations of knock-out mouse models have implicated cell cycle regulators like p18, p27, and Rb in MEN1-like disease. Screening for germ line mutation in such cell cycle regulator genes, and other candidates like the genes encoding menin interacting proteins, could uncover novel causes of MEN1-like states.

References

– Pellegata NS, et al. Germ-line mutations in p27Kip 1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proc Nat Acad Sci USA 103: 15558-15563,2006 (Correction: Proc Nat Acad Sci USA 103: 15558-15563,2006).
– Georgitsi M, et al. Germline CDKN 1 B/p27KIP1 mutation in multiple endocrine neoplasia.J (lin Endocrinol Metab 92: 3321-3325, 2007.
– Ozawa A, et al. The parathyroid/pituitary variant of MEN1 usually has causes other than p27Kip1 mutations. J (lin Endocrinol Metab 92: 1948-1951,2007.