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Mutation Profile of the MUT Gene in Chinese Methylmalonic Aciduria Patients

  • Mei-Ying Liu
  • Tze-Tze Liu
  • Yang-Ling Yang
  • Ying-Chen Chang
  • Ya-Ling Fan
  • Shu-Fen Lee
  • Yu-Ting Teng
  • Szu-Hui Chiang
  • Dau-Ming Niu
  • Shio-Jean Lin
  • Mei-Chun Chao
  • Shuan-Pei Lin
  • Lian-Shu Han
  • Yu Qi
  • Kwang-Jen HsiaoEmail author
Research Report
Part of the JIMD Reports book series (JIMD, volume 6)

Abstract

The mut-type methylmalonic aciduria (MMA, MIM 251000) is caused by a deficiency of mitochondrial methylmalonyl-CoA mutase (MCM, E.C. 5.4.99.2) 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.

Keywords

Disease Allele Methylmalonic Aciduria Neonatal Screening Program Major Deletion Significant Developmental Delay 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviation

MCM

Methylmalonyl-CoA mutase

MMA

Methylmalonic aciduria

Notes

Acknowledgments

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.

Supplementary material

301937_1_En_117_MOESM1_ESM.doc (107 kb)
MUT_Table 1_Oct 2011.doc (DOC 107 KB)
301937_1_En_117_MOESM2_ESM.doc (119 kb)
MUT_Table 2_Oct 2011.doc (DOC 119 KB)
301937_1_En_117_MOESM3_ESM.doc (44 kb)
MUT_Table 3_submit_0914.doc (DOC 44 KB)
301937_1_En_117_MOESM4_ESM.ppt (122 kb)
MUT_Suppl Fig_20110909.ppt (PPT 119 KB)

References

  1. Cartegni L, Wang J, Zhu Z, Zhang MQ, Krainer AR (2003) ESE finder: a web resource to identify exonic splicing enhancers. Nucleic Acids Res 31:3568–3571PubMedCrossRefGoogle Scholar
  2. Champattanachai V, Ketudat Cairns JR, Shotelersuk V, Keeratichamroen S, Sawangareetrakul P, Srisomsap C, Kaewpaluek V, Svasti J (2003) Novel mutations in a Thai patient with methylmalonic acidemia. Mol Genet Metab 79:300–302PubMedCrossRefGoogle Scholar
  3. Cooper DN, Youssoufian H (1988) The CpG dinucleotide and human genetic disease. Hum Genet 78:151–155PubMedCrossRefGoogle Scholar
  4. 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
  5. den Dunnen JT, Antonarakis SE (2000) Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Hum Mutat 15:7–12CrossRefGoogle Scholar
  6. Fowler B, Leonard JV, Baumgartner MR (2008) Causes of and diagnostic approach to methylmalonic acidurias. J Inherit Metab Dis 31:350–360PubMedCrossRefGoogle Scholar
  7. Gordon D, Abajian C, Green P (1998) Consed: a graphical tool for sequence finishing. Genome Res 8:195–202PubMedGoogle Scholar
  8. Hong CJ, Song HL, Lai HC, Tsai SJ, Hsiao KJ (1999) Methanol/acetone treatment helps the amplification of FMR1 CGG repeat fragment in dried blood spots from Guthrie cards. Lancet 353:1153–1154PubMedCrossRefGoogle Scholar
  9. Hori D, Hasegawa Y, Kimura M, Yang Y, Verma IC, Yamaguchi S (2005) Clinical onset and prognosis of Asian children with organic acidemias, as detected by analysis of urinary organic acids using GC/MS, instead of mass screening. Brain Dev 27:39–45PubMedCrossRefGoogle Scholar
  10. Horster F, Hoffmann GF (2004) Pathophysiology, diagnosis, and treatment of methylmalonic aciduria-recent advances and new challenges. Pediatr Nephrol 19:1071–1074PubMedCrossRefGoogle Scholar
  11. Janata J, Kogekar N, Fenton WA (1997) Expression and kinetic characterization of methylmalonyl-CoA mutase from patients with the mut- phenotype: evidence for naturally occurring interallelic complementation. Hum Mol Genet 6:1457–1464PubMedCrossRefGoogle Scholar
  12. Kikuchi M, Hanamizu H, Narisawa K, Tada K (1989) Assay of methylmalonyl CoA mutase with high-performance liquid chromatography. Clin Chim Acta 184:307–313PubMedCrossRefGoogle Scholar
  13. Lempp TJ, Suormala T, Siegenthaler R, Baumgartner ER, Fowler B, Steinmann B, Baumgartner MR (2007) Mutation and biochemical analysis of 19 probands with mut0 and 13 with mut- methylmalonic aciduria: identification of seven novel mutations. Mol Genet Metab 90:284–290PubMedCrossRefGoogle Scholar
  14. Liu TT, Hsiao KJ, Lu SF, Wu SJ, Wu KF, Chiang SH, Liu XQ, Chen RG, Yu WM (1998) Mutation analysis of the 6-pyruvoyl-tetrahydropterin synthase gene in Chinese hyperphenylalaninemia caused by tetrahydrobiopterin synthesis deficiency. Hum Mutat 11:76–83PubMedCrossRefGoogle Scholar
  15. 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
  16. Nickerson DA, Tobe VO, Taylor SL (1997) PolyPhred: automating the detection and genotyping of single nucleotide substitutions using fluorescence-based resequencing. Nucleic Acids Res 25:2745–2751PubMedCrossRefGoogle Scholar
  17. Niu DM, Chien YH, Chiang CC, Ho HC, Hwu WL, Kao SM, Chiang SH, Kao CH, Liu TT, Chiang H, Hsiao KJ (2010) Nationwide survey of extended newborn screening by tandem mass spectrometry in Taiwan. J Inherit Metab Dis 33:S295–S305PubMedCrossRefGoogle Scholar
  18. Perez B, Rincon A, Jorge-Finnigan A, Richard E, Merinero B, Ugarte M, Desviat LR (2009) Pseudoexon exclusion by antisense therapy in methylmalonic aciduria (MMAuria). Hum Mutat 30(12):1676–1682PubMedCrossRefGoogle Scholar
  19. Rincon A, Aguado C, Desviat LR, Sanchez-Alcudia R, Ugarte M, Perez B (2007) Propionic and methylmalonic acidemia: antisense therapeutics for intronic variations causing aberrantly spliced messenger RNA. Am J Hum Genet 81:1262–1270PubMedCrossRefGoogle Scholar
  20. Rosenblatt DS, Aspler AL, Shevell MI, Pletcher BA, Fenton WA, Seashore MR (1997) Clinical heterogeneity and prognosis in combined methylmalonic aciduria and homocystinuria (cblC). J Inherit Metab Dis 20:528–538PubMedCrossRefGoogle Scholar
  21. Worgan LC, Niles K, Tirone JC, Hofmann A, Verner A, Sammak A, Kucic T, Lepage P, Rosenblatt DS (2006) Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype. Hum Mutat 27:31–43PubMedCrossRefGoogle Scholar
  22. 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

Copyright information

© SSIEM and Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Mei-Ying Liu
    • 1
  • Tze-Tze Liu
    • 2
    • 3
  • Yang-Ling Yang
    • 4
  • Ying-Chen Chang
    • 2
  • Ya-Ling Fan
    • 3
  • Shu-Fen Lee
    • 1
  • Yu-Ting Teng
    • 1
  • Szu-Hui Chiang
    • 5
  • Dau-Ming Niu
    • 6
    • 7
  • Shio-Jean Lin
    • 10
  • Mei-Chun Chao
    • 8
    • 9
  • Shuan-Pei Lin
    • 11
    • 12
    • 13
  • Lian-Shu Han
    • 14
  • Yu Qi
    • 15
  • Kwang-Jen Hsiao
    • 3
    • 5
    Email author
  1. 1.Institute of GeneticsNational Yang-Ming UniversityTaipei, TaiwanRepublic of China
  2. 2.Genome Research CenterNational Yang-Ming UniversityTaipei, TaiwanRepublic of China
  3. 3.Department of Education and ResearchTaipei City HospitalTaipei, TaiwanRepublic of China
  4. 4.Department of PediatricsPeking University First HospitalBeijingChina
  5. 5.Department of Medical Research and EducationTaipei Veterans General HospitalTaipei, TaiwanRepublic of China
  6. 6.Departments of PediatricsTaipei Veterans General HospitalTaipei, TaiwanRepublic of China
  7. 7.Institute of Clinical MedicineNational Yang-Ming UniversityTaipei, TaiwanRepublic of China
  8. 8.Division of Genetics, Endocrinology and Metabolism, Department of PediatricsKaohsiung Medical University HospitalKaohsiung, TaiwanRepublic of China
  9. 9.Department of Medical GeneticsCollege of Medicine, Kaohsiung Medical UniversityKaohsiung, TaiwanRepublic of China
  10. 10.Genetic CenterNational Cheng Kung University HospitalTainan, TaiwanRepublic of China
  11. 11.Departments of PediatricsMackay Memorial HospitalTaipei, TaiwanRepublic of China
  12. 12.Department Medical ResearchMackay Memorial HospitalTaipei, TaiwanRepublic of China
  13. 13.Mackay MedicineNursing and Management CollegeTaipei, TaiwanRepublic of China
  14. 14.Department of Pediatric Endocrinology and Genetic Metabolism, Shanghai Institute for Pediatric ResearchXinhua Hospital, Shanghai Jiaotong University School of MedicineShanghaiChina
  15. 15.Central LaboratoryPeking University First HospitalBeijingChina

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