Variable hyperhomocysteinaemia phenotype in heterozygotes for the Gly307Ser mutation in cystathionine beta-synthase

Background: A deficiency of cystathionine beta-synthase (CBS) activity is the most frequent cause of homocystinuria, an autosomal recessive disease with multiple clinical manifestations. Mutations in the CBS gene have been reported in several patients with homocystinuria. Aims: To establish the molecular basis of CBS deficiency in a female patient with pyridoxine non-responsive homocystinuria, and to apply the findings to genetic screening of her family members. Methods: The entire coding region of the CBS cDNA was amplified by PCR and used for direct sequence analysis. Mutant alleles were confirmed by direct sequence analysis of PCR-amplified genomic DNA, and by a combination of single strand conformation polymorphism and temperature gradient gel electrophoresis analysis. Results: The proband was homozygous for a G(9I9)A base transition which predicts the substitution of serine for glycine at codon 307 in the CBS protein (G307S). The parents (both of Irish background) were heterozygotes for the C307S allele, while an asymptomatic sibling had normal CBS sequence. Plasma homocysteine, assessed after an oral methionine load, indicated the mother clearly had mo derate hyperhomocysteinaemia, whereas the father had normal concentrations of homocysteine. This is the first report of a normal methionine load test in a proven heterozygote for a CBS mutation which causes severe homocystinuria in the homozygote. Other factor(s) may have contributed to hyperhomocysteinaemia in the mother. The G307S allele has been reported in other patients and appears to be a common allele among families of Celtic origin.