The cystathionine β‐synthase (CBS) mutation c.1224‐2A>C in Central Europe: Vitamin B 6 nonresponsiveness and a common ancestral haplotype

In homocystinuria due to cystathionine β‐synthase (CBS) deficiency, vitamin B 6 response has been linked to distinct mutations and ruled out for others. The splice site mutation c.1224‐2A>C leading to the deletion of exon 12 is predominantly found in patients from Central Europe, where it has been found on in average 14% of mutant alleles. In this study we analyzed the clinical picture in 17 CBS deficient carriers of c.1224‐2A>C. Homozygotes for c.1224‐2A>C did not respond to vitamin B 6 , while in compound heterozygotes the response to vitamin B 6 depended on the mutation on the second allele. Maximum likelihood analysis revealed one common haplotype of the c.1224‐2A>C alleles. Additionally, we report the four novel CBS mutations c.451G>A (p.Gly151?), c.740_769del (p.Lys247_Gly256del), c.862G>C (p.Ala288Pro) and c.1135C>T (p.Arg379Trp). In summary, the data of this study suggest that the CBS c.1224‐2A>C allele confers vitamin B6 nonresponsiveness and that this mutant allele came from a common ancestor. © 2004 Wiley‐Liss, Inc.