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 â‰Š 3.3 Ã— 10-3), is âˆ¼20-fold higher than expected on the basis of the observed number of symptomatic homocystinuria patients carrying this mutation (qc.833C â‰Š 0.18 Ã— 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].
|Tipologia:||Articolo su rivista|
|Citazione:||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].|
|IF:||Con Impact Factor ISI|
|Settore Scientifico Disciplinare:||Settore BIO/18 - Genetica|
|Revisione (peer review):||Sì, ma tipo non specificato|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1002/humu.20430|
|Stato di pubblicazione:||Pubblicato|
|Data di pubblicazione:||2007|
|Titolo:||Diversity of cystathionline beta-synthase haplotypes bearing the most common homocystinuria mutation c.833T > C: A possible role for gene conversion|
|Autori:||Vyletal, P; Sokolova, J; Cooper, DN; Kraus, JP; Krawczak, M; Pepe, G; Rickards, O; Koch, HG; Linnebank, M; Kluijtmans, LAJ; Blom, J; Boers, GHJ; Gaustadnes, M; Skovby, F; Wilcken, B; Wilcken, DEL; Andria, G; Sebastio, G; Naughten, ER; Yap, S; Ohura, T; Pronicka, E; Laszlo, A; Kozich, V|
|Appare nelle tipologie:||01 - Articolo su rivista|