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Endocrine Abstracts (2013) 31 OC5.1 | DOI: 10.1530/endoabs.31.OC5.1

Academic Endocrine Unit, OCDEM, University of Oxford, Oxford, UK.


Multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder characterised by the occurrence of parathyroid, pancreatic islet and anterior pituitary tumours, is due to mutations of a tumour suppressor gene, MEN1. MEN1 mutations have also been reported to cause familial isolated primary hyperparathyroidism (FIHP). Moreover, 15 identical MEN1 mutations have been reported to cause MEN1 or FIHP in unrelated families; thereby implicating a role for genetic modifiers in the expression of the MEN1 mutation. To elucidate the role of genetic modifiers, we utilised a mouse knockout model for MEN1 in which <90% of heterozygous mice, lacking one Men1 allele that has exons 1 and 2 deleted (Men1+/−), develop parathyroid, pancreatic islet and anterior pituitary tumours, by the age of 18 months. Men1+/− mice were backcrossed for 10-18 generations to produce two congenic strains that had ≥99.9% genetic identity to either the C57BL/6 or 129S6/SvEv strain, and the pituitaries and pancreata and were examined for tumour development in 207 Men1+/− mice (81 males; 126 females), aged 18-26 months. This revealed that the frequency of pituitary tumours was influenced by the background strain. Thus, in female Men1+/− mice aged over 18 months, anterior pituitary tumours (expressing prolactin and growth hormone) were significantly more frequent in C57BL/6 than in 129S6/SvEv mice (78.8 vs 38.3% respectively; P<0.005); whereas, the frequency of pancreatic islet cell tumours in the two strains was similar (males 90.2 vs 97.5% and females 95.0 vs 87.9%; P>0.2). However, immunohistochemical examination of pancreatic islet tumours (n=25) revealed that glucagon-immunostaining tumours developed significantly more frequently in the 129S6/SvEv than the C57BL/6 strain (70.0 vs 6.7% respectively; P<0.002). Thus, our results demonstrate that genetic modifiers in the two mouse strains, 129S6/SvEv and C57BL/6, are able to alter the phenotypic expression of pituitary and pancreatic neuroendocrine tumours due to Men1 mutations.

Declaration of funding

This work was supported by the Medical Research Council (grant numbers G1000467, 2010-2015 and G0501780, 2006-2009) and the Wellcome Trust (grant number 087332/Z/08/Z, 2008-2011).

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