Abstract
Fragile X Syndrome (FXS) is associated with an unstable CGG repeat sequence in the 5’ untranslated region in the first exon of the FMR1 gene which resides at chromosome position Xq27.3 and is coincident with the fragile site FRAXA. The CGG sequence is polymorphic with respect to size and purity of the repeat. Interpopulation variation in the polymorphism of the FMR1 gene and consequently, in the predisposition to FXS due to the prevalence of certain unstable alleles has been observed. Spanish Basque population is distributed among narrow valleys in northeastern Spain with little migration between them until recently. This characteristic may have had an effect on allelic frequency distributions. We had previously reported preliminary data on the existence of FMR1 allele differences between two Basque valleys (Markina and Arratia). In the present work we extended the study to Uribe, Gernika, Durango, Goierri and Larraun, another five isolated valleys enclosing the whole area within the Spanish Basque region. We analyzed the prevalence of FMR1 premutated and intermediate/grey zone alleles. With the aim to complete the previous investigation about the stability of the Fragile X CGG repeat in Basque valleys, we also analyzed the existence of potentially unstable alleles, not only in relation with size and purity of CGG repeat but also in relation with DXS548 and FRAXAC1 haplotypes implicated in repeat instability. The data show that differences in allele frequencies as well as in the distribution of the mutational pathways previously identified are present among Basques. The data also suggest that compared with the analyzed Basque valleys, Gernika had increased frequency of susceptibility to instability alleles, although the prevalence of premutation and intermediate/grey zone alleles in all the analyzed valleys was lower than that reported in Caucasian populations.
Highlights
The Fragile X Syndrome (FXS, OMIM 309550) is an inherited form of mental retardation and is linked with a rare fragile site on the long arm of the X chromosome at Xq27.3 (FRAXA)
In the vast majority of the affected individuals it is caused primarily by a single type of mutation. This mutation is the unstable expansion of a CGG trinucleotide repeat sequence found in the 5 ́untranslated region in the first exon of the Fragile X Mental Retardation-1 (FMR1) gene [1]
This characteristic may have had an effect on allelic frequency distributions and in the incidence of Fragile X mutation associated diseases.We had previously reported preliminary data on the existence of FMR1 allele differences between two Basque valleys (Markina and Arratia) [32]
Summary
The Fragile X Syndrome (FXS, OMIM 309550) is an inherited form of mental retardation and is linked with a rare fragile site on the long arm of the X chromosome at Xq27.3 (FRAXA). In the vast majority of the affected individuals it is caused primarily by a single type of mutation. This mutation is the unstable expansion of a CGG trinucleotide repeat sequence found in the 5 ́untranslated region in the first exon of the Fragile X Mental Retardation-1 (FMR1) gene [1]. The CGG sequence is polymorphic with respect to size and purity of the repeat. Single AGG triplets that are variable in both number and location interrupt the CGG repeat of FMR1 in normal chromosomes. A single AGG interrupts the repeat sequence every 9-10 CGG repeats [2,3]
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