Homozygosity or compound heterozygosity for the c.833T>C transition (p.I278T) 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 (qc.833C ≊ 3.3 × 10-3), is ∼20-fold higher than expected on the basis of the observed number of symptomatic homocystinuria patients carrying this mutation (qc.833C ≊ 0.18 × 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.

Vyletal, P., Sokolova, J., Cooper, D.N., Kraus, J.P., Krawczak, M., Pepe, G., et al. (2007). Diversity of cystathionline beta-synthase haplotypes bearing the most common homocystinuria mutation c.833T > C: A possible role for gene conversion. HUMAN MUTATION, 28(3), 255-264 [10.1002/humu.20430].

Diversity of cystathionline beta-synthase haplotypes bearing the most common homocystinuria mutation c.833T > C: A possible role for gene conversion

RICKARDS, OLGA;
2007

Abstract

Homozygosity or compound heterozygosity for the c.833T>C transition (p.I278T) 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 (qc.833C ≊ 3.3 × 10-3), is ∼20-fold higher than expected on the basis of the observed number of symptomatic homocystinuria patients carrying this mutation (qc.833C ≊ 0.18 × 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.
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/18 - Genetica
English
Con Impact Factor ISI
CBS; Cystathionine beta-synthase; Gene conversion; Haplotype; Homocysteine; Homocystinuria; Pyridoxal 5′phosphate
Vyletal, P., Sokolova, J., Cooper, D.N., Kraus, J.P., Krawczak, M., Pepe, G., et al. (2007). Diversity of cystathionline beta-synthase haplotypes bearing the most common homocystinuria mutation c.833T > C: A possible role for gene conversion. HUMAN MUTATION, 28(3), 255-264 [10.1002/humu.20430].
Vyletal, P; Sokolova, J; Cooper, D; Kraus, J; Krawczak, M; Pepe, G; Rickards, O; Koch, H; Linnebank, M; Kluijtmans, L; Blom, J; Boers, G; Gaustadnes, M; Skovby, F; Wilcken, B; Wilcken, D; Andria, G; Sebastio, G; Naughten, E; Yap, S; Ohura, T; Pronicka, E; Laszlo, A; Kozich, V
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/34833
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