title: The cystathionine beta-synthase (CBS) mutation c.1224-2A>C in Central Europe: Vitamin B6 nonresponsiveness and a common ancestral haplotype.
abstract: In homocystinuria due to cystathionine beta-synthase (CBS) deficiency, vitamin B6 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 B6, while in compound heterozygotes the response to vitamin B6 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.
authors.affiliation: University Hospital Muenster, Dept. Pediatrics, Muenster, Germany. Michael.Linnebank@ukb.uni-bonn.de
authors.forename: Michael
authors.initials: M
authors.lastname: Linnebank
authors.forename: Miroslav
authors.initials: M
authors.lastname: Janosik
authors.forename: Viktor
authors.initials: V
authors.lastname: Kozich
authors.forename: Ewa
authors.initials: E
authors.lastname: Pronicka
authors.forename: Jolanta
authors.initials: J
authors.lastname: Kubalska
authors.forename: Jitka
authors.initials: J
authors.lastname: Sokolova
authors.forename: Anja
authors.initials: A
authors.lastname: Linnebank
authors.forename: Eva
authors.initials: E
authors.lastname: Schmidt
authors.forename: Christina
authors.initials: C
authors.lastname: Leyendecker
authors.forename: Thomas
authors.initials: T
authors.lastname: Klockgether
authors.forename: Jan Peter
authors.initials: JP
authors.lastname: Kraus
authors.forename: Hans Georg
authors.initials: HG
authors.lastname: Koch
mesh_terms: D000483:Alleles; D001317:Austria / Q000208:ethnology; D003541:Cystathionine beta-Synthase / Q000235:genetics* / Q000502:physiology; D004351:Drug Resistance / Q000235:genetics; D005061:Europe, Eastern / Q000208:ethnology; D005091:Exons / Q000235:genetics; D005260:Female; D018703:Founder Effect; D005838:Genotype; D005858:Germany / Q000208:ethnology; D006239:Haplotypes / Q000235:genetics; D006712:Homocystinuria / Q000188:drug therapy / Q000208:ethnology / Q000235:genetics*; D006801:Humans; D007585:Jews / Q000235:genetics; D016013:Likelihood Functions; D008297:Male; D020125:Mutation, Missense; D022821:RNA Splice Sites / Q000235:genetics*; D017384:Sequence Deletion; D014421:Turkey / Q000208:ethnology; D025101:Vitamin B 6 / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D022821:RNA Splice Sites; D025101:Vitamin B 6; D003541:Cystathionine beta-Synthase