Clustering of mutations in methylmalonyl CoA mutase associated with mut[sup [minus]] methylmalonic acidemia
Journal Article
·
· American Journal of Human Genetics; (United States)
OSTI ID:6821667
- Baylor College of Medicine, Houston, TX (United States)
Mutations have been described in human methylmalonyl CoA mutase (MCM) that exhibit partial defects in enzyme activity, including cobalamin-dependent (i.e., mut[sup [minus]]) or interallelic complementation. This work describes mutations in cells from four patients, three of whom exhibit a cobalamin-dependent phenotype and all four of whom exhibit interallelic complementation. Four novel mutations (R694W, G648D, G630E, and G626C) are identified that cluster near the carboxyl terminus of the protein, a region close to another mut[sup [minus]] mutation (G717V). Each of these mutations was shown to express a phenotype congruent with that of the parental cell line, after transfection into mut[sup 0] fibroblasts, and each exhibits interallelic complementation in cotransfection assays with clones bearing an R93H mutation. The activity of mutant enzymes expressed in Saccharomyces cerevisiae parallels the residual activity of the parental cell lines and exhibits novel sensitivities to pH and salt. The clustering of these mutations identifies a region of MCM that most likely represents the cobalamin-binding domain. The location of this domain, as well as the pattern of sequence preservation between the homologous human and Probionobacterium shermanii enzymes, suggests a mechanism for interallelic complementation in which the cobalamin-binding defect is complemented in trans from the heterologous subunits of the dimer. 35 refs., 8 figs., 2 tabs.
- OSTI ID:
- 6821667
- Journal Information:
- American Journal of Human Genetics; (United States), Journal Name: American Journal of Human Genetics; (United States) Vol. 55:1; ISSN AJHGAG; ISSN 0002-9297
- Country of Publication:
- United States
- Language:
- English
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