The ret proto-oncogene encodes a receptor tyrosine kinase whose ligands belong 
to the glial cell line-derived neurotrophic factor (GDNF) protein family. Its 
germline mutations are responsible for the development of multiple endocrine 
neoplasia (MEN) types 2A and 2B and Hirschsprung's disease (HSCR). MEN2A and 
MEN2B mutations result in the constitutive activation of Ret by different 
molecular mechanisms. MEN2A mutations involve cysteine residues present in the 
Ret extracellular domain and induce disulfide-linked Ret dimerization on the 
cell surface. MEN2B mutations were identified in methionine 918 in the tyrosine 
kinase domain and activate Ret without dimerization, probably due to a 
conformational change of its catalytic core region. In contrast to MEN2 
mutations, HSCR mutations represent loss of function mutations. We found that 
most of HSCR mutations detected in the extracellular domain impair the Ret cell 
surface expression. More interestingly, ret mutations in cysteines 618 and 620 
were reported in several families who developed both MEN2A and HSCR. It was 
suggested that these mutations might have two biological effects on Ret 
function, leading to the development of different clinical phenotypes in the 
same patients.