Mutation Profile of the MUT Gene in Chinese Methylmalonic Aciduria Patients
The mut-type methylmalonic aciduria (MMA, MIM 251000) is caused by a deficiency of mitochondrial methylmalonyl-CoA mutase (MCM, E.C. 18.104.22.168) activity, which results from defects in the MUT gene. To elucidate the mutation spectrum of the MUT gene in Chinese MMA patients, 13 exons of the MUT gene, including untranslated regions, were analyzed by PCR-based sequencing for 42 unrelated Chinese MMA patients. All the 42 patients were found to have at least one MUT mutation. A total of 41 mutations were identified. Of these mutations, 20 were novel ones, including one nonsense mutation (c.103C>T), 12 missense mutations (c.316A>C, c.424A>G, c.494A>G, c.554C>T, c.599T>C, c.919T>C, c.1009T>C, c.1061C>T, c.1141G>A, c.1208G>A, c.1267G>A, and c.1295A>C), one duplication (c.755dupA), three small deletions (c.398_399delGA, c.1046_1058del, and c.1835delG), two mutations that might affect mRNA splicing (c.754-1G>A and c.1084-10A>G), and one major deletion. Among the mutations identified, the c.1280G>A (15.5%), c.729_730insTT (10.7%), c.1106G>A (4.8%), c.1630_1631GG>TA (4.8%), and c.2080C>T (4.8%) accounted for 40% of the diseased alleles. The c.1280G>A and c.729_730insTT mutations were found to be the most frequent mutations in Southern and Northern Chinese, respectively. The results of microsatellite analysis suggest that the spread of c.729_730insTT among the Northern Chinese and of c.1280G>A and c.1630_1631GG>TA among the Southern Chinese may have undergone founder effects. This mutation analysis of the gene responsible for mut-type MMA will help to provide a molecular diagnostic aid for differential diagnosis of MMA and could be applied for carrier detection and prenatal diagnosis among Chinese family at risk of mut-type MMA.
KeywordsDisease Allele Methylmalonic Aciduria Neonatal Screening Program Major Deletion Significant Developmental Delay
The authors thank Sequencing Core of Genome Research Center of National Yang-Ming University for sequencing works and Dr. S.-F. Tsai for discussion and various helpful suggestions. This study was partially supported by the National Health Research Institutes and, in part, by grants from the National Science Council (NSC92-2320-B-010-076) and the Bureau of Health Promotion, Department of Health (DOH94-HP-2204 and DOH95-HP-2206), Taiwan, Republic of China.
- Crane AM, Ledley FD (1994) Clustering of mutations in methylmalonyl CoA mutase associated with mut- methylmalonic acidemia. Am J Hum Genet 55: 42–50Google Scholar
- Merinero B, Perez B, Perez-Cerda C, Rincon A, Desviat LR, Martinez MA, Sala PR, Garcia MJ, Aldamiz-Echevarria L, Campos J, Cornejo V, Del Toro M, Mahfoud A, Martinez-Pardo M, Parini R, Pedron C, Pena-Quintana L, Perez M, Pourfarzam M, Ugarte M (2008) Methylmalonic acidaemia: examination of genotype and biochemical data in 32 patients belonging to mut, cblA or cblB complementation group. J Inherit Metab Dis 31:55–66PubMedCrossRefGoogle Scholar
- Zwickler T, Lindner M, Aydin HI, Baumgartner MR, Bodamer OA, Burlina AB, Das AM, DeKlerk JB, Gokcay G, Grunewald S, Guffon N, Maier EM, Morava E, Geb S, Schwahn B, Walter JH, Wendel U, Wijburg FA, Muller E, Kolker S, Horster F (2008) Diagnostic work-up and management of patients with isolated methylmalonic acidurias in European metabolic centres. J Inherit Metab Dis 31:361–367PubMedCrossRefGoogle Scholar