title: Diversity of cystathionine beta-synthase haplotypes bearing the most common homocystinuria mutation c.833T>C: a possible role for gene conversion.
abstract: Homozygosity or compound heterozygosity for the c.833T>C transition (p.I278 T) in the cystathionine beta-synthase (CBS) gene represents the most common cause of pyridoxine-responsive homocystinuria in Western Eurasians. However, the frequency of the pathogenic c.833C allele, as observed in healthy newborns from several European countries (q(c.833C) approximately equals 3.3 x 10(-3)), is approximately 20-fold higher than expected on the basis of the observed number of symptomatic homocystinuria patients carrying this mutation (q(c.833C) approximately equals 0.18 x 10(-3)), implying clinical underascertainment. Intriguingly, the c.833C mutation is also present in combination with a 68-bp insertion, c.[833C; 844_845ins68], in a substantial proportion of chromosomes from nonhomocystinuric individuals worldwide. We have sought to study the relationship between the pathogenic and nonpathogenic c.833C-bearing chromosomes and to determine whether the pathogenic c.[833C; -] chromosomes are identical-by-descent or instead arose by recurrent mutation. Initial haplotype analysis of 780 randomly selected Czech and sub-Saharan African wild-type chromosomes, employing 12 intragenic markers, revealed 29 distinct CBS haplotypes, of which 10 carried the c.[833C; 844_845ins68] combination; none carried an isolated c.833C or c.844_845ins68 mutation. Subsequent examination of 69 pathogenic c.[833C; -] chromosomes, derived from homocystinuria patients of predominantly European origin, disclosed three unrelated haplotypes that differed from their wild-type counterparts by virtue of the presence of c.833C, thereby indicating that c.833T>C transition has occurred repeatedly and independently in the past. Since c.833T does not reside within an obvious mutational hotspot, we surmise that the three pathogenic and comparatively prevalent c.[833C; -] chromosomes may have originated by recurrent gene conversion employing the common nonpathogenic c.[833C; 844_845ins68] chromosomes as templates.
authors.affiliation: Center for Applied Genomics, Institute of Inherited Metabolic Disorders, Charles University 1st Faculty of Medicine, Prague, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Vyletal
authors.forename: Jitka
authors.initials: J
authors.lastname: Sokolová
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
authors.forename: Jan P
authors.initials: JP
authors.lastname: Kraus
authors.forename: Michael
authors.initials: M
authors.lastname: Krawczak
authors.forename: Guglielmina
authors.initials: G
authors.lastname: Pepe
authors.forename: Olga
authors.initials: O
authors.lastname: Rickards
authors.forename: Hans G
authors.initials: HG
authors.lastname: Koch
authors.forename: Michael
authors.initials: M
authors.lastname: Linnebank
authors.forename: Leo A J
authors.initials: LA
authors.lastname: Kluijtmans
authors.forename: Henk J
authors.initials: HJ
authors.lastname: Blom
authors.forename: Godfried H J
authors.initials: GH
authors.lastname: Boers
authors.forename: Mette
authors.initials: M
authors.lastname: Gaustadnes
authors.forename: Flemming
authors.initials: F
authors.lastname: Skovby
authors.forename: Bridget
authors.initials: B
authors.lastname: Wilcken
authors.forename: David E L
authors.initials: DE
authors.lastname: Wilcken
authors.forename: Generoso
authors.initials: G
authors.lastname: Andria
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Sebastio
authors.forename: Eileen R
authors.initials: ER
authors.lastname: Naughten
authors.forename: Sufin
authors.initials: S
authors.lastname: Yap
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Ohura
authors.forename: Ewa
authors.initials: E
authors.lastname: Pronicka
authors.forename: Aranka
authors.initials: A
authors.lastname: Laszlo
authors.forename: Viktor
authors.initials: V
authors.lastname: Kozich
mesh_terms: D000349:Africa; D001483:Base Sequence; D003541:Cystathionine beta-Synthase / Q000235:genetics*; D005060:Europe; D005785:Gene Conversion / Q000502:physiology*; D005787:Gene Frequency; D005820:Genetic Testing; D014644:Genetic Variation; D006239:Haplotypes; D006712:Homocystinuria / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data
chemical_list: D003541:Cystathionine beta-Synthase