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Haplotype analysis of MEN 2 mutations
E Gardner1, L M Mulligan, C Eng
1Department of Pathology, University of Cambridge, UK.
Abstract:
Multiple endocrine neoplasia type 2 (MEN 2) is a dominantly inherited cancer syndrome which affects thyroid C cells, and with variable frequency, the adrenal medulla, parathyroid and enteric autonomic ganglia. The syndrome is due to germline mutation in the receptor tyrosine kinase gene, RET. We have recently shown an unexpected correlation between one particular RET mutation, cys634-->arg, and the probability of parathyroid involvement in families with MEN 2A. Here we use haplotype analysis in the families to show that this correlation is not explained by a single founder chromosome which carries both the cys634-->arg mutation and a separate allele conferring susceptibility to parathyroid abnormality, but is probably due to the cys634-->arg mutation itself. The results also indicate that new mutations to MEN 2 are not infrequent.
Insights
Multiple endocrine neoplasia type 2 (MEN 2) is a genetic cancer syndrome caused by RET gene mutations. A specific RET mutation (cys634-->arg) is linked to parathyroid issues in MEN 2A patients.
Area of Science:
- Genetics
- Oncology
- Endocrinology
Background:
- Multiple endocrine neoplasia type 2 (MEN 2) is an inherited endocrine cancer syndrome.
- It is caused by germline mutations in the RET receptor tyrosine kinase gene.
- MEN 2 affects thyroid C cells, adrenal medulla, parathyroid glands, and enteric ganglia.
Purpose of the Study:
- To investigate the correlation between a specific RET mutation (cys634-->arg) and parathyroid involvement in MEN 2A.
- To determine if the correlation is due to the mutation itself or linked alleles.
Main Methods:
- Haplotype analysis was performed on families with MEN 2A.
- Genetic linkage analysis was used to examine the inheritance patterns of the RET mutation and parathyroid abnormalities.
Main Results:
- The cys634-->arg RET mutation is directly correlated with parathyroid involvement in MEN 2A.
- This correlation is not explained by a linked susceptibility allele but by the mutation itself.
- New RET mutations leading to MEN 2 occur with notable frequency.
Conclusions:
- The cys634-->arg RET mutation is a key determinant of parathyroid disease in MEN 2A.
- Understanding genotype-phenotype correlations is crucial for managing MEN 2.
- The incidence of new MEN 2 mutations warrants attention in genetic screening and counseling.