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

Authors :
et al.
Sokolova, J.
Cooper, D.N.
Kraus, J.P.
Krawczak, M.
Pepe, G.
Rickards, O
Koch, H.G.
Linnebank, M.
Kluijtmans, L.A.J.
Blom, H.J.
Boers, G.H.J.
Gaustadnes, M.
Skovby, F.
Wilcken, B.
Wilcken, D.E.L.
Andria, G.
Sebastio, G.
Naughten, E.R.
Yap, S.
Ohura, T.
Pronicka, E.
Laszlo, A.
Kozich, V.
et al.
Sokolova, J.
Cooper, D.N.
Kraus, J.P.
Krawczak, M.
Pepe, G.
Rickards, O
Koch, H.G.
Linnebank, M.
Kluijtmans, L.A.J.
Blom, H.J.
Boers, G.H.J.
Gaustadnes, M.
Skovby, F.
Wilcken, B.
Wilcken, D.E.L.
Andria, G.
Sebastio, G.
Naughten, E.R.
Yap, S.
Ohura, T.
Pronicka, E.
Laszlo, A.
Kozich, V.
Source :
Human Mutation; 255; 264; 1059-7794; 3; 28; ~Human Mutation~255~264~~~1059-7794~3~28~~
Publication Year :
2007

Abstract

Contains fulltext : 52383.pdf (publisher's version ) (Closed access)<br />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.

Details

Database :
OAIster
Journal :
Human Mutation; 255; 264; 1059-7794; 3; 28; ~Human Mutation~255~264~~~1059-7794~3~28~~
Publication Type :
Electronic Resource
Accession number :
edsoai.on1247216940
Document Type :
Electronic Resource