Endocrine Abstracts (2007) 13 P19.1

Genetic background influences expression of Multiple Endocrine Neoplasia type 1 (MEN1) mutation, implicating a role for genetic modifiers

Manuel Lemos, Brian Harding & Rajesh Thakker

University of Oxford, Academic Endocrine Unit, Nuffield Department of Clinical Medicine, Oxford, United Kingdom.

The Multiple Endocrine Neoplasia type 1 (MEN1) gene is located on chromosome 11q13 and patients with mutations develop parathyroid, pancreatic and pituitary tumours. MEN1 mutations also cause familial isolated primary hyperparathyroidism (FIHP) and the same MEN1 mutations, in different families, can cause either FIHP or MEN1. This emphasises the importance of genetic background in altering the expression of a mutation, and suggests the presence of genetic modifiers. We have investigated for the effects of genetic background by use of a mouse model with a targeted disruption of the Men1 gene. Mice were kept in accordance with UK Home Office welfare guidelines and project license restrictions. Heterozygous Men1+/− mice, which developed MEN1-associated tumours, were used in matings over five generations to establish, with >95% genetic homogeneity, the Men1 mutant allele on C57BL/6 and 129S6/SvEv strains. These Men1+/− mice were intercrossed to obtain homozygous Men1−/− mice. However, among 44 neonates no viable Men1−/− mice were obtained, and the distribution of Men1+/+: Men1+/−: Men1−/− genotypes was 14:30:0, and hence significantly deviated (P<0.001) from the expected Mendelian 1:2:1 ratio. Analysis of 411 embryos obtained at 10.5 to 16.5 days post-coitum (dpc) revealed that significant (P<0.05) deviations from the expected Mendelian ratio started to occur from 12.5 dpc and 15.5 dpc in the 129S6/SvEv and C57BL/6 strains, respectively. Moreover, viable Men1−/− embryos were absent by 13.5 dpc and 15.5 dpc in the 129S6/SvEv and C57BL/6 strains, respectively, thereby indicating an earlier lethality by 2 days in the 129S6/SvEv strain (Fishers test P=0.003). The causes of embryonic lethality included cardiovascular and hepatic abnormalities as well as neural tube defects. Thus, our findings, which reveal a function for the Men1 gene in embryonic development, demonstrate the importance of genetic background in influencing the expression of the mutant Men1 allele and implicate the role of genetic modifiers.

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