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Closely linked cis-acting modifier of expansion of the CGG repeat in high risk FMR1 haplotypes

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...

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Autores principales: Ennis, S, Murray, A, Brightwell, G, Morton, NE, Jacobs, PA
Formato: Texto
Lenguaje:English
Publicado: Wiley Subscription Services, Inc., A Wiley Company 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2683060/
https://www.ncbi.nlm.nih.gov/pubmed/17674408
http://dx.doi.org/10.1002/humu.20600
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author Ennis, S
Murray, A
Brightwell, G
Morton, NE
Jacobs, PA
author_facet Ennis, S
Murray, A
Brightwell, G
Morton, NE
Jacobs, PA
author_sort Ennis, S
collection PubMed
description 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 ∼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 ([Image: see text] , p=0.00002). We have verified that this SNP acts as a marker of repeat expansion in three independent samples. Hum Mutat 28(12), 1216–1224, 2007. © 2007 Wiley-Liss, Inc.
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spelling pubmed-26830602009-05-20 Closely linked cis-acting modifier of expansion of the CGG repeat in high risk FMR1 haplotypes Ennis, S Murray, A Brightwell, G Morton, NE Jacobs, PA Hum Mutat Research Article 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 ∼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 ([Image: see text] , p=0.00002). We have verified that this SNP acts as a marker of repeat expansion in three independent samples. Hum Mutat 28(12), 1216–1224, 2007. © 2007 Wiley-Liss, Inc. Wiley Subscription Services, Inc., A Wiley Company 2007-12 2007-08-02 /pmc/articles/PMC2683060/ /pubmed/17674408 http://dx.doi.org/10.1002/humu.20600 Text en Copyright © 2007 Wiley-Liss, Inc., A Wiley Company
spellingShingle Research Article
Ennis, S
Murray, A
Brightwell, G
Morton, NE
Jacobs, PA
Closely linked cis-acting modifier of expansion of the CGG repeat in high risk FMR1 haplotypes
title Closely linked cis-acting modifier of expansion of the CGG repeat in high risk FMR1 haplotypes
title_full Closely linked cis-acting modifier of expansion of the CGG repeat in high risk FMR1 haplotypes
title_fullStr Closely linked cis-acting modifier of expansion of the CGG repeat in high risk FMR1 haplotypes
title_full_unstemmed Closely linked cis-acting modifier of expansion of the CGG repeat in high risk FMR1 haplotypes
title_short Closely linked cis-acting modifier of expansion of the CGG repeat in high risk FMR1 haplotypes
title_sort closely linked cis-acting modifier of expansion of the cgg repeat in high risk fmr1 haplotypes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2683060/
https://www.ncbi.nlm.nih.gov/pubmed/17674408
http://dx.doi.org/10.1002/humu.20600
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