Molecular basis of phenotype expression in homocystinuria

Summary Cystathionine β‐synthase (CBS) deficiency is the most common cause of homocystinuria in humans. The human gene maps to chromosome 21q22.3 and encodes the CBS subunit of 551 amino acid residues (63 kDa). CBS, a tetramer of these subunits, binds its two substrates, homocysteine and serine, and three additional ligands: pyridoxal 5′‐phosphate, S ‐adenosylmethionine, and haem. Screening for mutations by expressing patient cDNA segments in E. coli permitted us to separate the parental CBS alleles, localize each mutation within one third of the cDNA, and functionally analyse the mutant protein. Using this method we identified the first 14 mutations in homocystinuria. The most common mutation in patients of predominantly ‘Celtic’ origin is the G 919 A transition which substitutes serine for glycine 307.