Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype

Authors

  • Lisa C. Worgan,

    1. Department of Human Genetics, McGill University, Montreal, Quebec, Canada
    2. Department of Medicine, McGill University, Montreal, Quebec, Canada
    3. McGill University Health Center, Montreal, Quebec, Canada
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  • Kirsten Niles,

    1. Department of Biology, McGill University, Montreal, Quebec, Canada
    2. McGill University Health Center, Montreal, Quebec, Canada
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  • Jamie C. Tirone,

    1. Department of Human Genetics, McGill University, Montreal, Quebec, Canada
    2. Department of Medicine, McGill University, Montreal, Quebec, Canada
    3. McGill University Health Center, Montreal, Quebec, Canada
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    • Jamie C. Tirone is deceased.

  • Adam Hofmann,

    1. Department of Human Genetics, McGill University, Montreal, Quebec, Canada
    2. Department of Medicine, McGill University, Montreal, Quebec, Canada
    3. McGill University Health Center, Montreal, Quebec, Canada
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  • Andrei Verner,

    1. McGill University and Genome Quebec Innovation Center, McGill University, Montreal, Quebec, Canada
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  • Alya'a Sammak,

    1. McGill University and Genome Quebec Innovation Center, McGill University, Montreal, Quebec, Canada
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  • Terrence Kucic,

    1. Department of Human Genetics, McGill University, Montreal, Quebec, Canada
    2. Department of Medicine, McGill University, Montreal, Quebec, Canada
    3. McGill University Health Center, Montreal, Quebec, Canada
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  • Pierre Lepage,

    1. McGill University and Genome Quebec Innovation Center, McGill University, Montreal, Quebec, Canada
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  • David S. Rosenblatt

    Corresponding author
    1. Department of Human Genetics, McGill University, Montreal, Quebec, Canada
    2. Department of Biology, McGill University, Montreal, Quebec, Canada
    3. Department of Medicine, McGill University, Montreal, Quebec, Canada
    4. McGill University Health Center, Montreal, Quebec, Canada
    • Division of Medical Genetics, MUHC-Montreal General Hospital, 1650 Cedar Ave. L3.319, Montreal, Quebec, Canada, H3G 1A4
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  • Communicated by Jan P. Kraus

Abstract

Cobalamin nonresponsive methylmalonic acidemia (MMA, mut complementation class) results from mutations in the nuclear gene MUT, which codes for the mitochondrial enzyme methylmalonyl CoA mutase (MCM). To better elucidate the spectrum of mutations that cause MMA, the MUT gene was sequenced in 160 patients with mut MMA. Sequence analysis identified mutations in 96% of disease alleles. Mutations were found in all coding exons, but predominantly in exons 2, 3, 6, and 11. A total of 116 different mutations, 68 of which were novel, were identified. Of the 116 different mutations, 53% were missense mutations, 22% were deletions, duplications or insertions, 16% were nonsense mutations, and 9% were splice-site mutations. Sixty-one of the mutations have only been identified in one family. A novel mutation in exon 2, c.322C>T (p.R108C), was identified in 16 of 27 Hispanic patients. SNP genotyping data demonstrated that Hispanic patients with this mutation share a common haplotype. Three other mutations were seen exclusively in Hispanic patients: c.280G>A (p.G94R), c.1022dupA, and c.970G>A (p.A324T). Seven mutations were seen almost exclusively in black patients, including the previously reported c.2150G>T (p.G717V) mutation, which was identified in 12 of 29 black patients. Two mutations were seen only in Asian patients. Some frequently identified mutations were not population-specific and were identified in patients of various ethnic backgrounds. Some of these mutations were found in mutation clusters in exons 2, 3, 6, and 11, suggesting a recurrent mutation. Hum Mutat 27(1), 31–43, 2006. © 2005 Wiley-Liss, Inc.

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