Diversity of cystathionine β-synthase haplotypes bearing the most common homocystinuria mutation c.833T>C: a possible role for gene conversion
✍ Scribed by Petr Vyletal; Jitka Sokolová; David N. Cooper; Jan P. Kraus; Michael Krawczak; Guglielmina Pepe; Olga Rickards; Hans G. Koch; Michael Linnebank; Leo A. J. Kluijtmans; Henk J. Blom; Godfried H. J. Boers; Mette Gaustadnes; Flemming Skovby; Bridget Wilcken; David E. L. Wilcken; Generoso Andria; Gianfranco Sebastio; Eileen R. Naughten; Sufin Yap; Toshihiro Ohura; Ewa Pronicka; Aranka Laszlo; Viktor Kožich
- Publisher
- John Wiley and Sons
- Year
- 2007
- Tongue
- English
- Weight
- 391 KB
- Volume
- 28
- Category
- Article
- ISSN
- 1059-7794
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✦ Synopsis
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 (q~c.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 (q~c.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. Hum Mutat 28(3), 255–264, 2007. Published 2006 Wiley-Liss, Inc.†