MOLECULAR-GENETICS OF TRANSKETOLASE IN THE PATHOGENESIS OF THE WERNICKE-KORSAKOFF-SYNDROME

Thiamine deficiency, a frequent complication of alcoholism, plays an i mportant role in the pathogenesis of the Wernicke-Korsakoff syndrome [ WKS]. Previous work by a number of investigators has implicated the th iamine-utilizing enzyme transketolase [Tk] as being involved mechanist ically in the genetic predisposition to WKS. In particular, Tk derived from fibroblasts has been found to have an increased K-m app for its cofactor thiamine pyrophosphate [TPP] and/or exist in different isoele ctric forms in alcoholic patients with WKS as compared with unaffected individuals. We have demonstrated that these differences are not due to different Tk alleles, tissue-specific Tk isozymes, or differential mRNA splicing. These findings point to other mechanisms to explain the biochemical Tk variants, such as differences in assembly of the funct ional holoenzyme or differences in modification of the primary transla tion product. Tk assembly or modification, once biochemically characte rized, may be found to be subject to genetic variation.