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Menopause is a period of women’s life characterized by the cessation of menses in a definitive way. The mean age for menopause is approximately 51 years. Primary ovarian insufficiency (POI) refers to ovarian dysfunction defined as irregular menses and elevated gonadotrophin levels before or at the age of 40 years. The etiology of POI is unknown but several genes have been reported as being of significance. The fragile X mental retardation 1 gene (FMR1) is one of the most important genes associated with POI. The FMR1 gene contains a highly polymorphic CGG repeat in the 5′ untranslated region of exon 1. Four allelic forms have been defined with respect to CGG repeat length and instability during transmission. Normal (5–44 CGG) alleles are usually transmitted from parent to offspring in a stable manner. The full mutation form consists of over 200 repeats, which induces hypermethylation of the FMR1 gene promoter and the subsequent silencing of the gene, associated with Fragile X Syndrome (FXS). Finally, FMR1 intermediate (45–54 CGG) and premutation (55–200 CGG) alleles have been principally associated with two phenotypes, fragile X tremor ataxia syndrome (FXTAS) and fragile X primary ovarian insufficiency (FXPOI).

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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.

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