Mutation and biochemical analysis of 19 probands with mut⁰ and 13 with mut⁻ methylmalonic aciduria: Identification of seven novel mutations

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• 作者：Thomas J. Lempp ; Terttu Suormala ; Renate Siegenthaler ; E. Regula Baumgartner ; Brian Fowler ; Beat Steinmann ; Matthias R. Baumgartner
• 关键词：Methylmalonic acid ; Methylmalonyl-CoA mutase ; MUT ; Organic aciduria
• 刊名：Molecular Genetics and Metabolism
• 出版年：2007
• 期刊代码：175_10967192
• 类别：bio
• 出版时间：March 2007
• 卷：90
• 期：3
• 页码：284-290
• 文件大小：368 K

摘要

Isolated methylmalonic acidurias (MMA-urias) comprise a group of rare autosomal recessively inherited disorders characterised by accumulation of MMA in urine and other body fluids, resulting from deficient activity of the mitochondrial enzyme methylmalonyl-CoA mutase (MCM). Isolated MMA-uria results from either MCM apoenzyme defects (mut⁰ and mut⁻) or defects in synthesis of its cofactor 5-deoxyadenosylcobalamin, i.e. cblA, cblB and cblD-variant 2. To date various studies have identified 171 disease-causing mutations in the MCM gene (MUT). We report mutation analysis in 32 probands with mut MMA-uria including 13 probands with a mut⁻ defect. Sixty two of 64 possible mutant alleles were identified, seven of which were novel missense alleles. We found three novel mutations (c.427C>T/p.H143Y; c.862T>C/p.S288P; c.1361G>A/p.G454E) among 19 probands with a mut⁰ defect and four novel mutations (c.299A>G/p.Y100C; c.1031C>T/p.S344F; c.1097A>G/p.N366S; c.2081G>T/p.R694L) among 13 probands with a mut⁻ defect. Our study provides evidence that the p.Y100C, p.R108H, p.N366S, p.V633G, p.R694W, p.R694L and p.M700K mutations are associated with a mut⁻ phenotype.