Human Molecular Genetics, 2002, Vol. 11, No. 26 3361-3369
© 2002 Oxford University Press
Identification of the gene responsible for the cblB complementation group of vitamin B12-dependent methylmalonic aciduria
1Department of Biochemistry and Molecular Biology, University of Calgary, Canada, 2Department of Human Genetics and 3Department of Medicine, McGill University, Montreal, Canada, 4McGill University Health Center, McGill University, Montreal, Canada and 5Montreal Genome Center, Montreal, Canada
Received September 27, 2002; Accepted October 25, 2002
The methylmalonic acidurias are metabolic disorders resulting from deficient methylmalonyl-CoA mutase activity, a vitamin B12-dependent enzyme. We have cloned the gene for the cblB complementation group caused by deficient activity of a cob(I)alamin adenosyltransferase. This was accomplished by searching bacterial genomes for genes in close proximity to the methylmalonyl-CoA mutase gene that might encode a protein with the properties of an adenosyltransferase. A candidate was identified in the Archaeoglobus fulgidus genome and was used to probe the human genome database. It yielded a gene on chromosome 12q24 that encodes a predicted protein of 250 amino acids with 45% similarity to PduO in Salmonella enterica, a characterized cob(I)alamin adenosyltransferase. A northern blot revealed an RNA species of 1.1 kb predominating in liver and skeletal muscle. The gene was evaluated for deleterious mutations in cblB patient cell lines. Several mutations were identified including a 5 bp deletion (5del572gggcc576), two splice site mutations (IVS2–1G>T, IVS3–1G>A), andt several point mutations (A135T, R186W, R191W and E193K). Two additional amino acid substitutions (R19Q and M239K) were found in several patient cell lines but were found to be common polymorphisms (36% and 46%) in control alleles. The R186W mutation, which we suggest is disease-linked, is present in four of the six patient cell lines examined (homoallelic in two) and in 4 of 240 alleles in control samples. These data confirm that the identified gene, MMAB, corresponds to the cblB complementation group and has the appearance of a cob(I)alamin adenosyltransferase, as predicted from biochemical data.
* To whom correspondence should be addressed at: Department of Biochemistry and Molecular Biology, Room 250, Heritage Medical Research Building, 3330 Hospital Drive NW, Calgary, AB, Canada T2N 4N1. Tel: 403 2202268; Fax: 403 2108115; Email: rgravel{at}ucalgary.ca
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