Human Molecular Genetics, Vol 6, 2213-2221, Copyright © 1997 by Oxford University Press
CE Kim, PM Gallagher, AB Guttormsen, H Refsum, PM Ueland, L Ose, I Folling, AS Whitehead, MY Tsai and WD Kruger
Cystathionine beta-synthase (CBS) deficiency is an autosomal recessive
disorder which results in extremely elevated levels of total plasma
homocysteine (tHcy) and high risk of thromboembolic events. About half of
all patients diagnosed with CBS deficiency respond to pyridoxine treatment
with a significant lowering of tHcy levels. We examined 12 CBS-deficient
patients from 10 Norwegian families for mutations in the CBS gene and
identified mutations in 18 of the 20 CBS alleles. Five of the seven
patients classified as pyridoxine-responsive contain the newly identified
point mutation, G797A (R266K). This point mutation is tightly linked with a
previously identified 'benign' 68 bp duplication of the intron 7-exon 8
boundary within the CBS gene. We tested the effect of all of the mutations
identified on human CBS function utilizing a yeast system. Five of the six
mutations had a distinguishable phenotype in yeast, indicating that they
were in fact pathogenic. Interestingly, the G797A allele had no phenotype
when the yeast were grown in high concentrations of pyridoxine, but a
severe phenotype when grown in low concentrations, thus mirroring the
behavior in humans. These studies show that the G797A mutation is an
important cause of pyridoxine-responsive CBS deficiency and demonstrate the
utility of yeast functional assays in the analysis of human mutations.
ARTICLES
Functional modeling of vitamin responsiveness in yeast: a common pyridoxine-responsive cystathionine beta-synthase mutation in homocystinuria
Division of Population Science, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
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