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human papillary thyroid carcinomas this gene showed rearrangements (Grieco et aI., 1990).
The RET gene encodes a transmembrane tyrosine kinase protein with an as yet unknown
ligand.
In the dominantly inherited cancer syndromes multiple endocrine neoplasia type 2
(MEN 2A and B), familial medullary carcinoma (FMTC) , and the dominantly inherited
Hirschsprung's disease, which is a developmental disorder, specific mutations have been
found in the RET proto-oncogene (Donis-Keller et aI., 1993; Mulligan et aI., 1993a; Edery
et aI., 1994; Hofstra et aI., 1994; Romeo et aI., 1994). MEN 2 and FMTC are characterized
by the development of bilateral medullary thyroid carcinoma (MTC). In both MEN 2A and
B pheochromocytomas are observed and in MEN 2B a distinct more aggressive and complex
phenotype is apparent (Nanes and Catherwood, 1992). Hirschsprung's disease is
characterized by congenital absense of parasympathetic innervation in the lower intestinal
tract and cancer-association has never been described. The mutations observed in the RET
gene might explain the distict clinical phenotypes. The MEN2A and FMTC mutations were
aU missense mutations involving the 4 conserved cysteines in the extracellular region and
probably interfere with ligand binding (Donis-Keller et aI., 1993; Mulligan et aI., 1993a,b).
In MEN2B all mutations found so far were specific threonine to methionine substitutions in
codon 918 in the intracellular tyrosine kinase domain of RET. The same mutation was also
observed in 6 sporadic MTC tumors (Hofstra et aI., 1994). The nature of the mutations found
in Hirschsprung's disease however are different. These include deletions, nonsense and
missense mutations and are presumably loss of function mutations.
The RET mutations observed in the cancer syndromes suggest that the gene is an
oncogene rather than a tumor suppressor gene because: 1) very specific heterozygous amino
acid substitutions were observed and 2) chromosome 10 allelic loss was hardly ever found
in these tumors (Landsvater et aI., 1989; Nelkin et aI., 1989; Mulligan et aI., 1993a,b).
However, the observation that the RET protein dimerizes (Bongarzone et aI., 1993;
Rodriguez and Park, 1993) suggests that a dominant-negative mechanism can not be ruled
out. The presumed loss of function mutations found in Hirschsprung's disease indicate that
haplo-insufficiency (dosage-effect) is the underlying mechanism. Homozygous RET gene
knockout mice die soon after birth and show impairment in kidney development and lack
enteric neurons throughout the digestive tract (Schuchardt et aI., 1994).
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