Methionine adenosyltransferase I/III de¢ciency:twoKoreancompoundheterozygous siblings with a novel mutation S. Z. KIM 1 ,E.SANTAMARIA 2 ,T.E.JEONG 1 ,H.L.LEVY 3 ,J.M.MATO 2 , F. J. CORRALES 2 and S. H. MUDD 3 * 1 KoreaGeneticResearchCenter,CheongjuCity,Korea; 2 DivisionofHepatologyand Gene Therapy, University of Navarra, Pamplona, Spain; 3 Division of Genetics, Children’s Hospital, and the Department of Pediatrics, Harvard Medical School, Boston, Massachusetts; 4 Laboratory of Molecular Biology, National Institute of Mental Health, Bethesda, Maryland, USA *Correspondence: NIMH/DIRP/LMB, Building 36, Room 1B-08, 36 Convent Drive MSC 4034, Bethesda, MD 20892-4034, USA. E-mail: shm@codon.nih.gov MS received 23.09.02 Accepted 08.11.02 Summary: 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.Plasmatotalhomocysteine(tHcy)ismildlyelevated,butnotsomarkedly as to establish a diagnosis of homocystinuria due to cystathionine b-synthase (CBS) deficiency. CBS deficiency was ruled out by the presence of slightly elevated concentrations of plasma cystathionine. Although the plasma concen- trations 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 S.Z.KimandE.Santamariacontributedequallytothiswork.F.J.CorralesandS.H.Mudd shareseniorauthorship. J.Inherit.Metab.Dis. 25(2002)661^671 # SSIEMandKluwerAcademicPublishers.PrintedintheNetherlands. 661