Impact of patient mutations on heterodimer formation and function in human galactose-1-P uridylyltransferase.
Impairment of the human enzyme galactose-1-P uridylyltransferase (hGALT) results in the potentially lethal disorder, galactosemia. One of the fundamental questions with regard to this dimeric enzyme involves the possible influence of patient mutations on heterodimer formation and activity. Indeed, considering that many if not most galactosemia patients are compound heterozygotes, this is an issue of clinical as well as basic science interest. We have utilized a yeast expression system for the human enzyme to test whether each of a small number of mutations in hGALT (S135L, F171S, F171W, Q188R, N314D, and R333W) impact either heterodimer formation or function. Our results clearly demonstrate that while a majority of the alleles tested show precisely random patterns of subunit assortment, two deviate slightly but significantly from this pattern. Similarly, while some heterodimers exhibit apparent independence of subunit activity, others do not. These data not only demonstrate that common patient mutations in hGALT can influence both heterodimer formation and function in heterozygotes, they further raise the question of whether such interactions may also occur between different mutant alleles in compound heterozygotes (i.e., patients). Indeed, such influences may underlie some of the biochemical and clinical heterogeneity observed in the galactosemia patient population.
Christacos
Nicole C
NC
Graduate Program in Genetics and Molecular Biology, Emory University, Atlanta, GA, USA.
Fridovich-Keil
Judith L
JL
D019281:Dimerization; D005693:Galactosemias / Q000201:enzymology / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D009154:Mutation; D006599:UDPglucose-Hexose-1-Phosphate Uridylyltransferase / Q000235:genetics* / Q000378:metabolism; D015003:Yeasts / Q000235:genetics
D006599:UDPglucose-Hexose-1-Phosphate Uridylyltransferase