Diversity of cystathionine beta-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 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.
Vyletal
Petr
P
Center for Applied Genomics, Institute of Inherited Metabolic Disorders, Charles University 1st Faculty of Medicine, Prague, Czech Republic.
Sokolová
Jitka
J
Cooper
David N
DN
Kraus
Jan P
JP
Krawczak
Michael
M
Pepe
Guglielmina
G
Rickards
Olga
O
Koch
Hans G
HG
Linnebank
Michael
M
Kluijtmans
Leo A J
LA
Blom
Henk J
HJ
Boers
Godfried H J
GH
Gaustadnes
Mette
M
Skovby
Flemming
F
Wilcken
Bridget
B
Wilcken
David E L
DE
Andria
Generoso
G
Sebastio
Gianfranco
G
Naughten
Eileen R
ER
Yap
Sufin
S
Ohura
Toshihiro
T
Pronicka
Ewa
E
Laszlo
Aranka
A
Kozich
Viktor
V
D000349:Africa; D001483:Base Sequence; D003541:Cystathionine beta-Synthase / Q000235:genetics*; D005060:Europe; D005785:Gene Conversion / Q000502:physiology*; D005787:Gene Frequency; D005820:Genetic Testing; D014644:Genetic Variation; D006239:Haplotypes; D006712:Homocystinuria / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data
D003541:Cystathionine beta-Synthase