The influence of the Fragile X Mental Retardation-1 (FMR1) gene CGG repetitive region in the female reproductive function

• Autor(a) principal: Rodrigues, Bárbara Luísa Cerqueira
• Data de Publicação: 2018
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10773/22001
• topic: Reprodução humana - Mulheres; Ovários; Genética molecular

The impact of the Fragile Mental Retardation-1 (FMR1) gene CGG repeat number in the female reproductive function is well established. Carriers of a CGG repeat number between 55 and 200, designated a premutation, are prone to develop primary ovarian insufficiency or early menopause. Yet, an impact on the reproductive function in carriers of “normal” genotypes and sub-genotypes (CGG<54) is controversial. The presence of AGG in normal-sized alleles confers stability, hampering the expansion of the repeat number in future generations. To the best of our knowledge testing the influence of the AGG number and pattern on the female reproductive function has never been endeavored. Herein, the ovarian reserve markers were correlated with CGG number as well as AGG number and pattern, in female carriers of FMR1 normal-sized alleles. Our cohort comprised 50 healthy young females, candidates for oocyte donation. Considering AGG number and pattern are not routinely determined different methodologies were implemented: 1) Triplet-Primed Polymerase Chain Reaction; 2) Sanger sequencing; and 3) Restriction Fragment-Length Analysis. A projection of the association between the CGG repeat values and the hormonal levels, by multivariate analysis, was performed, considering the FMR1 new “normal” sub-genotypes previously defined. The hormonal levels associated with the different samples were not sufficient to discriminate the sub-genotypes, indicating that the individualization of the samples classified by sub-genotype was not possible. Resorting to a mathematical formula that determines the allelic score, taking into account total allele size, and AGG number and pattern. After statistical analysis, it was possible to divide the samples into two groups: a first called an equivalent group and a second called an opposite group. The equivalent group is composed mainly of samples carrying alleles in the normal FMR1 sub-genotype and the opposite, where most of the samples have an FMR1 low/normal sub-genotype. In the equivalent group, a positive and significant correlation was observed between the number of antral follicles and the hormonal levels: prolactin and luteinizing hormone (LH). Thus, it is possible to predict the largest number of antral follicles produced combining the levels of prolactin and LH. These results actually confirm prior publications as the low/normal sub-genotype has been previously associated with a diminished ovarian reserve. Overall, this study confirms the association of the FMR1 CGG repetitive region in the female reproductive function and suggests that the stability of the alleles is a determining factor for the ovarian response success.