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

Homozygosity or compound heterozygosity for the c.833T > C transition (p.I278 T) in the cystathionine betas 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) congruent to 3.3 x 10(-3)), is similar to 20-fold higher than expected on the basis of the observed number of symptomatic homocystinuria. patients carrying this mutation (qc.833C congruent to 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.