Mutations of the ret protooncogene in German multiple endocrine neoplasia families: Relation between genotype and phenotype.

It has been suggested that not only the position but also the
nature of the mutations of the ret protooncogene strongly correlate
with the clinical manifestation of the multiple endocrine neoplasm
type 2 (MEN 2) syndrome. In particular, individuals with a
Cys634-Arg substitution should have a greater risk of developing
parathyroid disease. We, therefore, analyzed 94 unrelated families
from Germany with inherited medullary thyroid carcinoma (MTC) for
mutation of the ret protooncogene. In all but 1 of 59 families with
MEN 2A, germline mutations in the extracellular domain of the ret
protein were found. Some 81% of the MEN 2A mutations affected codon
634. Phenotype-genotype correlations suggested that the prevalence
of pheochromocytoma and hyperparathyroidism is significantly higher
in families with codon 634 mutations, but there was no correlation
with the nature of the mutation. In all but 1 of 27 familial MTC
(FMTC) families, mutations were detected in 1 of 4 cysteines in the
extracellular domain of the ret protooncogene. Half of the FMTC
mutations affected codon 634. Mutations outside of codon 634
occurred more often in FMTC families than in MEN 2A families. In
all but 1 of 8 MEN 2B patients, de novo mutations in codon 918 were
found. These data confirm the preferential localization of MEN
2-associated mutations and the correlation between disease
phenotype and the position of the ret mutation, but there was no
correlation between the occurrence of hyperparathyroidism or
pheochromocytoma and the nature of the mutation.