Biological effect of novel mutation of the RET gene associated with multiple endocrine neoplasia type 2.

Long isoform RET constructs carrying either double mutation or Ala641Ser alone were transfected to NIH3T3 fibroblasts. NIH3T3 cells with double mutation showed high transforming and clonogenic potential . Carriers of dual mutation are at high risk of MTC development.However, based on transforming properties Ala641Ser can by considered as RET mutation class A with low transforming potential. Penetrance of class A mutations need not be 100%. Activation of RET and subsequent tumor formation can occur by second hit causing dominant effect of mutated allele. MTC could develop later, at patients' higher age, so lifetime monitoring of patients is recommended. Novel method TOXCAT has been found as the in vivo approach enables to determine the changes in extent of transmembrane domain. Ala641 change affected dimerization of RET receptors by increased association of affected TMs. The modification to Ser can boost the non-covalent interaction by forming the tetrad of Ser in the same side of ?-helical RET TM.