HUMAN METHIONINE SYNTHASE - CDNA CLONING AND IDENTIFICATION OF MUTATIONS IN PATIENTS OF THE CBLG COMPLEMENTATION GROUP OF FOLATE COBALAMIN DISORDERS/

Methionine synthase catalyzes the remethylation of homocysteine to met hionine in a methylcobalamin-dependent reaction, We used specific regi ons of homology within the methionine synthase sequences of several lo wer organisms to clone a human methionine synthase cDNA by a combinati on of RT-PCR and inverse PCR, The enzyme is 1265 amino acids in length and contains the seven residue structure-based sequence fingerprint i dentified for cobalamin-containing enzymes. The gene was localized to chromosome 1q43 by the FISH technique, We have identified one missense mutation and a 3 bp deletion in patients of the cblG complementation group of inherited homocysteine/folate disorders by SSCP and sequence analysis, as well as an amino acid substitution present in high freque ncy in the general population, We discuss the possibility that a mild deficiency of methionine synthase activity could be associated with mi ld hyperhomocysteinemia, a risk factor for cardiovascular disease and possibly neural tube defects.