The FMR1 premutation as a cause of premature ovarian failure in Brazilian women

Abstract

The loss-of-function mutation of the FMR1 gene due to expansion of the 5' UTR CGG repeat causes the fragile X syndrome, the most frequent form of inherited mental retardation. On the other hand, the FMR1 premutation, which is transcriptionally active and produces the protein, confers an increased risk for premature ovarian failure (POF) to carrier females. Among 41 unrelated Brazilian women with idiopathic POF, we found three carriers of premutations (CGG expansionse ³ 59 repeats) and two carriers of high-intermediate alleles (50-55 repeats). Two premutations and two intermediate alleles were detected among the 16 familial POF cases, and one premutated woman, among the 25 sporadic cases. The premutation frequency among the familial cases (12.5%) differed significantly from that found in a control group of 96 unrelated Brazilian women aged ³ 47 years, who had not experience POF and in which no premutations or high-intermediate alleles were detected. In the search for factors influencing the probability of a premutation carrier presenting POF, another 20 unrelated premutated women with POF, from fragile X families, were included in the study. The analysis of the FMR1-linked loci DXS548 and FRAXAC1 did not indicate any association of a particular haplotype with the occurrence of POF. An effect of X-inactivation skewing was not apparent in blood cells, and POF-associated premutations showed a wide range of repeat sizes, from 59, the smallest known to expand to full mutations upon transmission to offspring, to approximately 200.

Factores genéticos en la falla ovárica precoz.

“…Las mujeres que portan la premutación tienen FOP en 13 a 26% de los casos y la edad de la menopausia disminuye en proporción al número de repeticiones. Casi todas las mujeres con premutación, que experimentan FOP, heredaron la premutación de su padre y no de su madre (6) , indicando una influencia epigenética en su determinación (11) . Además, las mujeres afectadas tienen niveles elevados de FSH y niveles bajos de inhibina B, aún con ciclos menstruales regulares.…”

Research Article Molecular Diagnosis of X-Fragile Syndrome: Perspectives for the Public Health System in the Central Region of Brazil

“…FXS presents a broad spectrum of clinical manifestations, such as intellectual deficit, autism spectrum disorder, anxiety and withdrawal, language deficits, hyperactivity, aggressiveness, and self-aggressive behaviors. As for the morphological aspects, the presence of prominent articular hyperextensibility, prominent forehead and brow, high palate, large ears and macroorchidism at puberty are highlighted (Costa et al, 2006;River et al, 2010;Kwok et al 2016).…”

“…Until 1991, the gene responsible for FXS was unknown and the diagnosis was based only on cytogenetic techniques (Pastori et al, 2014). However, these tests are still ineffective in identifying less than 5% of the patients, in addition to not identifying the extent of CGG repeats (Costa et al, 2006;França et al, 2011). With the advancement of molecular techniques, it was possible to diagnose using the Southern Blot technique, through which it is possible to specify the approximate degree of expansion.…”

Standardization of capillary electrophoresis for diagnosis of fragile X syndrome in the Brazilian public health system

“…Therefore, a large number of these women are misdiagnosed or even undiagnosed. Another feature of FXS is the occurrence of patients with a premutation, commonly undiagnosed for not presenting significant clinical features of the syndrome, but who may have children with full mutation owing to new expansions .…”