Premature ovarian failure and FRAXA premutation: Positive correlation in a Brazilian survey

Abstract

Fragile X syndrome (FRAXA) is the most common form of inherited mental retardation (MR). The mutational mechanism leading to the disease involves an expansion of a trinucleotide repeat located at the 5' UTR region of the gene FMR-1. Four types of alleles can be identified in the population, based on the number of repeats: normal (6-40), gray-zone (41-60), premutated (61-200), and fully mutated (>200). Despite only full mutations being associated with the development of the disorder, some authors propose a correlation between FRAXA premutation and the occurrence of premature ovarian failure (POF). We have undertaken a study in 58 women from 24 fragile X syndrome families ascertained for FRAXA testing. Using Southern blotting for direct DNA analysis we have identified 19 normal, 33 premutation carriers, and 6 fully mutated individuals (including 4 somatic mosaics showing premutated and fully mutated alleles). Among the premutated women, 11 experienced menopause before the age of 40 (POF), including one somatic mosaic, which was different from the ones with normal pattern who did not experience POF. Our data corroborate the notion that females carrying alleles in the premutation range are at high risk of experiencing POF.

Expression of three zebrafish orthologs of human FMR1-related genes and their phylogenetic relationships

“…The full mutation results in reduction or complete loss of gene transcription and, therefore, loss of the activity of the protein it encodes, FMRP (Brown 2002;Verkerk et al 1991). The known range of FMR1 CGG repeat expansion-related phenotypes has recently become greater since moderate expansions to a "premutation" range of 50-200 repeats have been found to contribute to premature ovarian failure among female carriers (Hundscheid et al 2000;Machado-Ferreira et al 2004), a tremor/ataxia syndrome among aged male carriers and other neurological phenotypes (Hagerman et al 2001). The neurological premutation phenotypes appear to depend upon the expansion of the mRNA rather than changes in protein structure (Jin et al 2003).…”

Assessment of a clinical checklist in the diagnosis of fragile X syndrome in India

“…14,31 In our study, we observed premature ovarian failure in 78.5% of the carrier females with premutation (data not shown), a higher percentage than reported previously. 12,13 Because clinical features typical of FRAXA arise because of the full mutation and consequent methylation of the FMR1 5 0 UTR, clinical checklists can be used to effectively screen individuals with full mutation. In affected individuals, no correlation was observed between clinical severity as measured by clinical score and the number of CGG repeats (data not shown).…”

“…11 In addition, 21% to 33% of female premutation carriers experience premature ovarian failure. [12][13][14] All males with the full mutation are mentally retarded. About half of the females with the full mutation have mental subnormality or some mild phenotypic features of FRAXA.…”

Recomendaciones para el estudio genético de la pareja con alteraciones en la reproducción

“…El número de repeticiones no se relaciona con el retraso mental asociado al síndrome, sino que aumenta el riesgo creciente de IOP en las mujeres portadoras. Debido a la inestabilidad de la repetición sobre la transmisión de los alelos premutados, las mujeres presentan riesgo de tener niños afectados con síndrome de X fr agil 20 .…”