Closely linked cis-acting modifier of expansion of the CGG repeat in high risk FMR1 haplotypes.
Hum Mutat
; 28(12): 1216-24, 2007 Dec.
Article
em En
| MEDLINE
| ID: mdl-17674408
In its expanded form, the fragile X triplet repeat at Xq27.3 gives rise to the most common form of inherited mental retardation, fragile X syndrome. This high population frequency persists despite strong selective pressure against mutation-bearing chromosomes. Males carrying the full mutation rarely reproduce and females heterozygous for the premutation allele are at risk of premature ovarian failure. Our diagnostic facility and previous research have provided a large databank of X chromosomes that have been tested for the FRAXA allele. Using this resource, we have conducted a detailed genetic association study of the FRAXA region to determine any cis-acting factors that predispose to expansion of the CGG triplet repeat. We have genotyped SNP variants across a 650-kb tract centered on FRAXA in a sample of 877 expanded and normal X chromosomes. These chromosomes were selected to be representative of the haplotypic diversity encountered in our population. We found expansion status to be strongly associated with a approximately 50-kb region proximal to the fragile site. Subsequent detailed analyses of this region revealed no specific genetic determinants for the whole population. However, stratification of chromosomes by risk subgroups enabled us to identify a common SNP variant which cosegregates with the subset of D group haplotypes at highest risk of expansion (chi(1)(2)=17.84, p=0.00002). We have verified that this SNP acts as a marker of repeat expansion in three independent samples.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Haplótipos
/
Expansão das Repetições de Trinucleotídeos
/
Proteína do X Frágil da Deficiência Intelectual
/
Síndrome do Cromossomo X Frágil
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
/
Risk_factors_studies
Limite:
Female
/
Humans
/
Male
Idioma:
En
Revista:
Hum Mutat
Assunto da revista:
GENETICA MEDICA
Ano de publicação:
2007
Tipo de documento:
Article
País de afiliação:
Reino Unido