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Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype
Author(s) -
Worgan Lisa C.,
Niles Kirsten,
Tirone Jamie C.,
Hofmann Adam,
Verner Andrei,
Sammak Alya'a,
Kucic Terrence,
Lepage Pierre,
Rosenblatt David S.
Publication year - 2006
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20258
Subject(s) - genetics , biology , nonsense mutation , methylmalonic acidemia , missense mutation , mutation , exon , haplotype , compound heterozygosity , indel mutation , frameshift mutation , microbiology and biotechnology , gene , allele , genotype , single nucleotide polymorphism , endocrinology
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.