Characterization of six novel mutations in the methylenetetrahydrofolate reductase (MTHFR) gene in patients with homocystinuria

Severe deficiency of methylenotrtrahydrofolate reductase (MTHFR) is the mos t common inborn error of folate metabolism. Patients are characterized by s evere hyperhomocysteinemia, homocystinuria and a variety of neurological an d vascular problems, Eighteen rare mutations have been reported in this gro up of patients, Two polymorphisms which cause mild enzyme deficiencies have been described (677C-->T and 1298A-->C), The first sequence change encodes a thermolabile enzyme and is associated with mild hyperhomocysteinemia. Si x novel point mutations are described in patients with severe deficiency of MTHFR, along with their associated polymorphisms and clinical phenotypes. Of the two nonsense mutations (1762A-->T, 1134C-->G) and four missense muta tions (1727C-->T, 1172G-->A, 1768G-->A, and 358G-->A), one was identified i n the N-terminal catalytic domain, while the others were located in the reg ulatory C-terminal region. All four residues affected by missense mutations are conserved in one or more MTHFRs of other species, This report brings t he total to 24 mutations identified in severe MTHFR deficiency, with two mu tations identified in each of 22 patients, Hum Mutat 15:280-287, 2000, (C) 2000 Wiley Liss, Inc.