This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In the next funding period we will study structure-function in the human -phosphomannomutase 2 ( PMM2). This haloalkanoate dehalogenase superfamily (HADSF) phosphotransferase is required for GDP-mannose and dolichol-phosphate-mannose formation, and hence glycoprotein biosynthesis. Defects in phosphomannomutase are the cause of a serious congenital disorder, known as carbohydrate-deficient glycoprotein type 1a syndrome (CDG-Ia). This recently discovered genetic disease is caused by mutations in the PMM2 gene on chromosome 16p13. The most common mutant is R141H (40% of disease alleles of CDG-Ia patients), which has a high carrier frequency of 1/70 in the general population. This mutation is never observed as a homozygous form, suggesting that this combination is lethal. Numerous clinical genotypes have been identified, with the range of phenotypes extending from mild to severe. In the proposed studies we will study structure, catalysis and stability in wild-type and mutant forms of PMM2. In addition, the structure and function of PMM2 will be compared to those of the PMM1 isozyme. The goal of these studies is to correlate genotype with enzyme function and enzyme function with the clinical CDG-Ia phenotype.
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