title: The molecular basis of cystathionine beta-synthase (CBS) deficiency in UK and US patients with homocystinuria.
abstract: The molecular basis of cystathionine beta-synthase (CBS) deficiency has been studied in 536 patient alleles with 130 different mutations described. To date, no study has reported on the incidence of any of the reported mutations in patients from the UK and the US. We developed a new antisense oligonucleotide (ASO) PCR/hybridization method to screen for 12 of the most frequent CBS mutations in 14 unrelated patients from the UK and 38 unrelated patients from the US, a total of 104 independent alleles. We determined 16/28 (57%) and 28/76 (37%) of the affected alleles in the UK and US patients, respectively. Four different mutations were identified in the UK patients (c.374G>A, R125Q; c.430G>A, E144K; c.833T>C, I278T; c.919G>A, G307S) and 8 mutations identified in the patients from the US (c.341C>T, A114V; c.374G>A, R125Q; c.785C>T, T262M; c.797G>A, R266K; c.833T>C, I278T; c.919G>A, G307S; g.13217A>C (del ex 12); c.1330G>A, D444N). The I278T was the predominant mutation in both populations, present in 8 (29%) of 28 independent alleles from the UK and in 14 (18%) of 76 independent alleles from the US. The incidence of the G307S mutation was 21% in the UK patients and 8% in the US patients. The spectrum of mutations observed in the patients from the UK and US is closer to that which is observed in Northern Europe and bears less resemblance to that observed in Ireland.
authors.affiliation: Cardiovascular Sciences Research Group, University of Wales College of Medicine, Heath Park, Cardiff, UK.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Moat
authors.affiliation: Pediatrics and Cell Developmental Biology, University of Colorado School of Medicine, Denver, Colorado.
authors.forename: Liming
authors.initials: L
authors.lastname: Bao
authors.affiliation: Metabolic Unit, University Children's Hospital Basel, Basel, Switzerland.
authors.forename: Brian
authors.initials: B
authors.lastname: Fowler
authors.affiliation: Clinical Chemistry, Sheffield Children's Hospital, Sheffield, UK.
authors.forename: James R
authors.initials: JR
authors.lastname: Bonham
authors.affiliation: Willink Biochemical Genetics Unit, Royal Manchester Children's Hospital, Manchester, UK.
authors.forename: John H
authors.initials: JH
authors.lastname: Walter
authors.affiliation: Pediatrics and Cell Developmental Biology, University of Colorado School of Medicine, Denver, Colorado.
authors.forename: Jan P
authors.initials: JP
authors.lastname: Kraus
mesh_terms: D015331:Cohort Studies; D003541:Cystathionine beta-Synthase / Q000172:deficiency* / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods; D006712:Homocystinuria / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000235:genetics; D016133:Polymerase Chain Reaction / Q000379:methods; D006113:United Kingdom; D014481:United States
chemical_list: D016376:Oligonucleotides, Antisense; D003541:Cystathionine beta-Synthase