Methionine Adenosyltransferase I/III Deficiency: Two Korean Compound Heterozygous Siblings with a Novel Mutation

Two Korean sisters, one detected during neonatal screening, the other ascertained at age 3 years during family screening, have persistent hypermethioninaemia without elevation of plasma tyrosine or severe liver disease. Plasma total homocysteine (tHcy) is mildly elevated, but not so markedly as to establish a diagnosis of homocystinuria due to cystathionine beta-synthase (CBS) deficiency. CBS deficiency was ruled out by the presence of slightly elevated concentrations of plasma cystathionine. Although the plasma concentrations of methionine were markedly elevated, plasma S-adenosylmethionine (AdoMet) was not. This pattern of metabolic abnormalities suggested that the patients have deficient activity of methionine adenosyltransferase (MAT) in their livers (MAT I/III deficiency). Molecular genetic studies demonstrate that each patient is a compound heterozygote for two mutations in MAT1A, the gene that encodes the catalytic subunit that composes MAT I and MAT III: a previously known inactivating G378S point mutation, and a novel W387X truncating mutation. W387X mutant protein, expressed in E. coli and purified, has about 75% of wild-type activity. Negative subunit interaction between the mutant subunits is suggested to explain the hypermethioninaemia of these sisters. They have had normal growth and development and have no mental retardation, neurological abnormalities, or other clinical problems. They are the first individuals of Korean descent proven to have MAT I/III deficiency.