药物基因组学和药物蛋白质组学杂志

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Mutation Analysis of Methylmalonyl CoA Mutase Gene Exon 2 in Egyptian Families: Identification of 25 Novel Allelic Variants

Dina A Ghoraba, Magdy M Mohammed and Osama K Zaki

Methylmalonic aciduria (MMA) is an autosomal recessive disorder of methylmalonate and cobalamin (cbl; vitamin B₁₂) metabolism. It is an inborn error of organic acid metabolism results commonly from a defect in the gene encoding the methylmalonyl-CoA mutase apoenzyme (MCM). Here we report the results of mutation study of Exon 2 of MUT gene (coding MCM residues from 1 to 128) in ten unrelated Egyptian families affected with methylmalonic aciduria. Patients were presented with a wide-anion gap metabolic acidosis. The diagnosis has established by measurement of C3 (propionylcarnitine) and C3:C2 (propionylcarnitine/acetylcarnitine) in blood by tandem mass spectrometry, and confirmed by detection of abnormally elevated methylmalonic acid level in urine by gas chromatography-mass spectrometry GC/MS and by isocratic cation exchange “high-performance liquid-chromatography” (HPLC). Direct sequencing of gDNA of the MUT gene exon 2 has revealed a total of 26 allelic variants, ten of which were intronic, four were novel modifications predicted to affect splicing region, eight were located upstream to exon 2 coding region, three were novel mutations within coding region (c.15G>A (p.K5K), c.165C>A (p.N55K) and c.7del (p.R3EfsX14) and the last one was a previously reported mutation c.323G>A.