Mutation Study Essay

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Am. J. Hum. Genet. 55:42-50, 1994

Clustering of Mutations in Methylmalonyl CoA Mutase Associated with mut- Methylmalonic Acidemia
Ana Maria Crane' and Fred D. Ledley" 2
'Departments of Cell Biology and Pediatrics, Baylor College of Medicine, and 2GeneMedicine, Inc., Houston

Summary Mutations have been described in human methylmalonyl CoA mutase (MCM) that exhibit partial defects in enzyme activity, including cobalamin-dependent (i.e., muC) 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 mutT mutation (G717V). Each of these mutations was shown to express a phenotype congruent with that of the parental cell line, after transfection into mut0 fibroblasts, and each exhibits interallelic complementation in cotransfection assays with clones bearing a R93H mutation. The activity of mutant enzymes expressed in Saccharomyces cerevisiac 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 cobalaminbinding defect is complemented in trans from the heterologous subunits of the dimer.

Introduction A variety of naturally occurring mutations in human methylmalonyl CoA mutase (MCM; E.C.5.4.99.2) have provided insights into the genetics and function of this enzyme. MCM is a mitochondrial matrix enzyme and is a homodimer of 78,489-dalton subunits that requires adenosylcobalamin (ado-cbl) as a cofactor (Retey 1982). Inherited deficiency of this enzyme causes a disorder of organic
Received November 5, 1993; accepted for publication March 8, 1994. Address for correspondence and reprints: Dr. Fred D. Ledley, Department of Cell Biology, Baylor College of Medicine, One Baylor Plaza,
Houston, TX 77030. © 1994 by The American Society of Human Genetics. All rights reserved.
0002-9297/94/5501-0007$02.00

acid metabolism, termed "mut methylmalonic acidemia" (mut MMA; McKusick 251000) (McKusick 1990). Two classes of mutations in MCM are classically distinguished by studies of [14C]-propionate metabolism in primary fibroblasts from patients with mut MMA (Rosenberg and Fenton 1989; Ledley 1990). muto mutations are those in which there is no detectable MCM activity and no detectable ["4C]-propionate metabolism in cultured cells. mutmutations are those in which there is a low level of both residual enzyme activity and ["4C]-propionate incorporation. Commonly, this residual activity can be stimulated in cultured cells by administration of high concentrations of hydroxocobalamin (Willard and Rosenberg 1977, 1979a, 1979b). Studies of the enzyme activity in mut- fibroblasts suggest that MCM in these cells exhibits an increased Kmado-cbl (Willard and Rosenberg 1977, 1979a, 1979b). A variety of mutations in MCM have been discovered by molecular cloning of cDNAs from primary fibroblasts. Initial studies demonstrated that 20%-30% of alleles associated with muto forms of the disease produced abnormally low levels of MCM mRNA, indicative of a primary defect in mRNA transcription or processing (Ledley et al. 1990a). Several different muto mutations have been described in the amino-terminal half of the protein, and gene-transfer studies using clones bearing these mutations have demonstrated that each of these changes eliminates enzyme activity (Jansen and Ledley 1990; Ledley et al. 1990a). The initial cloning of cDNAs from cells with the mut- phenotype revealed that cells
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