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J. Biol. Chem., Vol. 277, Issue 9, 7136-7143, March 1, 2002

This Article Full Text Full Text (PDF) All Versions of this Article: 277/9/7136    most recent M111419200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pind, S. Articles by Natowicz, M. R. Search for Related Content PubMed PubMed Citation Articles by Pind, S. Articles by Natowicz, M. R. Social Bookmarking                      What's this?

V490M, a Common Mutation in 3-Phosphoglycerate Dehydrogenase Deficiency, Causes Enzyme Deficiency by Decreasing the Yield of Mature Enzyme^*

Steven Pind^§, Elzbieta Slominski, Jill Mauthe, Kayla Pearlman^¶, Kathryn J. Swoboda, John A. Wilkins^**, Patricia Sauder^**, and Marvin R. Natowicz^¶§§

From the  Department of Biochemistry and Medical Genetics and ^** Departments of Internal Medicine and Immunology, University of Manitoba, Winnipeg, Manitoba R3E 0W3, Canada, the ^¶ Division of Medical Genetics, Shriver Center for Mental Retardation, Waltham, Massachusetts 02452, the  Departments of Neurology and Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah 84132, and  Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts 02114

A deficiency of 3-phosphoglycerate dehydrogenase (PHGDH) is a disorder of serine biosynthesis identified in children with congenital microcephaly, seizures, and severe psychomotor retardation. We report here the identification of the 1468GA (V490M) mutation of this gene in two siblings of an Ashkenazi Jewish family, providing further evidence that the V490M mutation is a common, panethnic cause of this deficiency. Using a novel, DNA-based diagnostic test, the mutation was not detected in 400 non-Jewish controls; one heterozygote was found among 400 persons of Ashkenazi Jewish ethnicity. Extensive biochemical studies were undertaken to characterize the effect of this mutation on enzyme activity, turnover, and stability. The V490M PHGDH yielded less than 35% of the activity observed for the wild-type enzyme when overexpressed by transient transfection or when comparing the endogenous activity in fibroblast cells from the patients with controls. Immunoblotting studies showed a comparable reduction in the level of immunoreactive PHGDH in cells expressing the mutant enzyme. Pulse-chase experiments with metabolically labeled PHGDH indicated that this resulted from an increased rate of degradation of the mutant enzyme following its synthesis. Thermolability analyses of mutant and wild-type enzyme activity revealed no significant differences. While others have proposed that the V490M mutation decreases the V_max of the enzyme, we conclude that this mutation impairs the folding and/or assembly of PHGDH but has minimal effects on the activity or stability of that portion of the V490M mutant that reaches a mature conformation.

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