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Research Article Free access | 10.1172/JCI117166

Cloning and expression of mutations demonstrating intragenic complementation in mut0 methylmalonic aciduria.

A A Qureshi, A M Crane, N V Matiaszuk, I Rezvani, F D Ledley, and D S Rosenblatt

Department of Human Genetics, McGill University Montreal, Quebec, Canada.

Find articles by Qureshi, A. in: PubMed | Google Scholar

Department of Human Genetics, McGill University Montreal, Quebec, Canada.

Find articles by Crane, A. in: PubMed | Google Scholar

Department of Human Genetics, McGill University Montreal, Quebec, Canada.

Find articles by Matiaszuk, N. in: PubMed | Google Scholar

Department of Human Genetics, McGill University Montreal, Quebec, Canada.

Find articles by Rezvani, I. in: PubMed | Google Scholar

Department of Human Genetics, McGill University Montreal, Quebec, Canada.

Find articles by Ledley, F. in: PubMed | Google Scholar

Department of Human Genetics, McGill University Montreal, Quebec, Canada.

Find articles by Rosenblatt, D. in: PubMed | Google Scholar

Published April 1, 1994 - More info

Published in Volume 93, Issue 4 on April 1, 1994
J Clin Invest. 1994;93(4):1812–1819. https://doi.org/10.1172/JCI117166.
© 1994 The American Society for Clinical Investigation
Published April 1, 1994 - Version history
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Abstract

The mut0 mutation resulting in methylmalonyl CoA mutase (MCM) apoenzyme deficiency and methylmalonic aciduria is characterized by undetectable enzyme activity in cell extracts and low incorporation of propionate into cultured cells which is not stimulated by hydroxycobalamin. A mut0 fibroblast cell line (WG1681) from an African-American male infant complemented another mut0 cell line (WG 1130). Cloning and sequencing of cDNA from WG 1681 demonstrated compound heterozygosity for two novel changes at highly conserved sites: G623R and G703R. In addition, two previously described homozygous polymorphisms, H532R and V671I, were found. Hybridization of allele-specific oligonucleotides to PCR amplified MCM exons from the proband and family members identified a clinically normal mother, half-sister, and half-brother as carriers of the G703R change in cis with both polymorphisms. Transfection of each change into a mut0 cell line with very low MCM mRNA (GM1673) demonstrated a lack of stimulation of propionate uptake in the absence and presence of hydroxycobalamin. Cotransfection of each mutation with the previously identified R93H mutation of WG 1130 stimulated propionate uptake, indicating that G623R and G703R are independently capable of complementing the R93H mutation.

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