Cystathionine beta-synthase (
CBS) deficiency is the major cause of
homocystinuria in humans. The most frequent symptoms of
homocystinuria include: dislocated optic
lenses, vascular disorders, skeletal abnormalities and
mental retardation. Patients with this deficiency have elevated levels of homocyst(e)ine,
methionine and low
cysteine in their body fluids. These abnormal levels often partially or fully normalize upon treatment with pharmacological doses of
vitamin B6. To investigate the molecular and biochemical basis for these conditions, it was necessary to determine the
nucleotide and
polypeptide sequence of CBS. We report here the human CBS
cDNA sequence of 2,554
nucleotides encoding the CBS subunit of 551
amino acids. An intron of 214 bp appears to be retained in the 3'-untranslated region of most of the fibroblast and liver
mRNA. We also report a frequent Mspl polymorphism in the 3'-untranslated sequence and two synonymous mutations in the coding region: 699C/T (Y233Y) and 1080C/T (A360A). The amino acid sequence similarity of human and rat CBS is greater than 90%; the
enzyme also exhibits 52% similarity to
O-acetylserine(thiol)-lyase from bacteria and plants. Lastly, we demonstrate that expression of the human
enzyme in CHO cells yields enzymatically active
protein of the expected size with a half-life of approximately 14 hrs.