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

P Vyletal; J Sokolová; DN Cooper; JP Kraus; M Krawczak; G Pepe; O Rickards; HG Koch; LAJ Kluijtmans; HJ Blom; GHJ Boers; Mette Gaustadnes; F Skovby; B Wilcken; DEL Wilcken; G Andria; G Sebastio; ER Naughten; S Yap; T Ohura; E Pronicka; A Laszlo; V Kožich

doi:10.1002/humu.20430

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

P Vyletal, J Sokolová, DN Cooper, JP Kraus, M Krawczak, G Pepe, O Rickards, HG Koch, LAJ Kluijtmans, HJ Blom, GHJ Boers, Mette Gaustadnes, F Skovby, B Wilcken, DEL Wilcken, G Andria, G Sebastio, ER Naughten, S Yap, T OhuraE Pronicka, A Laszlo, V Kožich

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

18 Citations (Scopus)

Abstract

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.
Udgivelsesdato: March

Original language	English
Journal	Human Mutation
Volume	28
Issue	3
Pages (from-to)	255-264
Number of pages	10
ISSN	1059-7794
DOIs	https://doi.org/10.1002/humu.20430
Publication status	Published - 2007

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Vyletal, P., Sokolová, J., Cooper, DN., Kraus, JP., Krawczak, M., Pepe, G., Rickards, O., Koch, HG., Kluijtmans, LAJ., Blom, HJ., Boers, GHJ., Gaustadnes, M., Skovby, F., Wilcken, B., Wilcken, DEL., Andria, G., Sebastio, G., Naughten, ER., Yap, S., ... Kožich, V. (2007). Diversity of cystathionine ß-synthase haplotypes bearing the most common homocystinuria mutation c.833T>C: a possible role for gene conversion. Human Mutation, 28(3), 255-264. https://doi.org/10.1002/humu.20430

@article{7ab62fe00dc911dcbee902004c4f4f50,

title = "Diversity of cystathionine {\ss}-synthase haplotypes bearing the most common homocystinuria mutation c.833T>C: a possible role for gene conversion.",

abstract = "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. Udgivelsesdato: March",

author = "P Vyletal and J Sokolov{\'a} and DN Cooper and JP Kraus and M Krawczak and G Pepe and O Rickards and HG Koch and LAJ Kluijtmans and HJ Blom and GHJ Boers and Mette Gaustadnes and F Skovby and B Wilcken and DEL Wilcken and G Andria and G Sebastio and ER Naughten and S Yap and T Ohura and E Pronicka and A Laszlo and V Ko{\v z}ich",

year = "2007",

doi = "10.1002/humu.20430",

language = "English",

volume = "28",

pages = "255--264",

journal = "Human Mutation",

issn = "1059-7794",

publisher = "John Wiley & Sons Inc.",

number = "3",

}

Vyletal, P, Sokolová, J, Cooper, DN, Kraus, JP, Krawczak, M, Pepe, G, Rickards, O, Koch, HG, Kluijtmans, LAJ, Blom, HJ, Boers, GHJ, Gaustadnes, M, Skovby, F, Wilcken, B, Wilcken, DEL, Andria, G, Sebastio, G, Naughten, ER, Yap, S, Ohura, T, Pronicka, E, Laszlo, A & Kožich, V 2007, 'Diversity of cystathionine ß-synthase haplotypes bearing the most common homocystinuria mutation c.833T>C: a possible role for gene conversion.', Human Mutation, vol. 28, no. 3, pp. 255-264. https://doi.org/10.1002/humu.20430

Diversity of cystathionine ß-synthase haplotypes bearing the most common homocystinuria mutation c.833T>C: a possible role for gene conversion. / Vyletal, P; Sokolová, J; Cooper, DN et al.
In: Human Mutation, Vol. 28, No. 3, 2007, p. 255-264.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Diversity of cystathionine ß-synthase haplotypes bearing the most common homocystinuria mutation c.833T>C: a possible role for gene conversion.

AU - Vyletal, P

AU - Sokolová, J

AU - Cooper, DN

AU - Kraus, JP

AU - Krawczak, M

AU - Pepe, G

AU - Rickards, O

AU - Koch, HG

AU - Kluijtmans, LAJ

AU - Blom, HJ

AU - Boers, GHJ

AU - Gaustadnes, Mette

AU - Skovby, F

AU - Wilcken, B

AU - Wilcken, DEL

AU - Andria, G

AU - Sebastio, G

AU - Naughten, ER

AU - Yap, S

AU - Ohura, T

AU - Pronicka, E

AU - Laszlo, A

AU - Kožich, V

PY - 2007

Y1 - 2007

N2 - 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. Udgivelsesdato: March

AB - 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. Udgivelsesdato: March

U2 - 10.1002/humu.20430

DO - 10.1002/humu.20430

M3 - Journal article

C2 - 17072863

SN - 1059-7794

VL - 28

SP - 255

EP - 264

JO - Human Mutation

JF - Human Mutation

IS - 3

ER -