Single Nucleotide Polymorphism and FMR1 CGG Repeat Instability in Two Basque Valleys

Abstract

SummaryFragile X Syndrome (FXS, MIM 309550) is mainly due to the expansion of a CGG trinucleotide repeat sequence, found in the 5 untranslated region of the FMR1 gene. Some studies suggest that stable markers, such as single nucleotide polymorphisms (SNPs) and the study of populations with genetic identity, could provide a distinct advance to investigate the origin of CGG repeat instability. In this study, seven SNPs (WEX28 rs17312728:G>T, WEX70 rs45631657:C>T, WEX1 rs10521868:A>C, ATL1 rs4949:A>G, FMRb rs25707:A>G, WEX17 rs12010481:C>T and WEX10 ss71651741:C>T) have been analyzed in two Basque valleys (Markina and Arratia). We examined the association between these SNPs and the CGG repeat size, the AGG interruption pattern and two microsatellite markers (FRAXAC1 and DXS548). The results suggest that in both valleys WEX28-T, WEX70-C, WEX1-C, ATL1-G, and WEX10-C are preferably associated with cis-acting sequences directly influencing instability. But comparison of the two valleys reveals also important differences with respect to: (1) frequency and structure of "susceptible" alleles and (2) association between "susceptible" alleles and STR and SNP haplotypes. These results may indicate that, in Arratia, SNP status does not identify a pool of susceptible alleles, as it does in Markina. In Arratia valley, the SNP haplotype association reveals also a potential new "protective" factor.

Study of the Genetic Etiology of Primary Ovarian Insufficiency: FMR1 Gene

“…A research from Brightwell et al in 2002 [67] noted that association between SNP ATL1 (rs4949:A>G) and flanking microsatellite markers reflect the mutational history of CGG repeat expansion. Previous investigations of our group do not support this suggestion [68]. …”

Unique AGG Interruption in the CGG Repeats of the FMR1 Gene Exclusively Found in Asians Linked to a Specific SNP Haplotype

“…In contrast, the findings in African Americans using those three microsatellites and the SNP, ATL1 did not show a haplotype association with CGG repeats instability [ 29 ]. Also, our findings in this study support earlier studies where the SNP haplotype association between nearby SNPs and AGG interruption patterns in CGG repeats of the FMR1 gene likely reflects linkage disequilibrium in each population [ 9 , 17 , 30 ]. Therefore, it is difficult to determine if an associated haplotype is a real factor for CGG repeats instability or a linkage disequilibrium in a specific population [ 31 ].…”

Contraction of fully expanded FMR1 alleles to the normal range: predisposing haplotype or rare events?

“…19 In addition, normal-sized alleles with more than 24 pure CGGs at the 3′-end frequently share the typically studied DXS548-FRAXAC1 FXS haplotype, suggesting that these alleles could be more prone to expand. 15,17,20,21 FMR1 mosaicism has been reported, with multiple CGG repeat sizes (normal and full mutation alleles) present in different tissues (inter-tissue mosaic) or in different cells from the same tissue (intra-tissue mosaic) of a single patient. These post-zygotic events, utterly responsible for the intergenerational changes on repeat sizes when unstable alleles are further transmitted, may help to elucidate mitotic instability processes.…”