Influence of intermediate and uninterrupted FMR1 CGG expansions in premature ovarian failure manifestation.
BACKGROUND
Studies attempting to precisely define the range of fragile mental retardation 1 (FMR1) expansions and its inf luence in premature ovarian failure (POF) manifestation are partially lacking. To this aim, we evaluated a large cohort of POF patients for the size and, in selected cases, for the sequence of the CGG expansion. Furthermore, the correlation between POF and X-inactivation was investigated in FRAXA families.


METHODS
By fluorescent PCR, 190 POF and 200 control women were sized for the CGG tract; some subjects were also characterized by sequencing and for the FMR1 activation ratio.


CONCLUSIONS
We found a significant association (19/190, 10%, P < 1 x 10(-6)) between POF and FMR1 premutation (range 63-163 repeats) and a significant enrichment (9/190, 4.7%, P = 0.021) of POF carriers of intermediate expansions (range 41-58 repeats). Interestingly, intermediate alleles were entirely composed of CGG repeats. Furthermore, the analysis of three pairs of siblings with similar FMR1 expansions and discordant for the POF phenotype showed a direct correlation between the expression of the intermediate/premutated allele and POF manifestation. The results obtained strengthen the correlation between FMR1 expansion and POF and suggest that the manifestation of the ovarian dysfunction could be influenced both by the pattern of interruption of the CGG repeat and by X-inactivation.
Bodega
B
B
Department of Biology and Genetics for Medical Sciences, University of Milan, Milan, Italy.
Bione
S
S
Dalprà
L
L
Toniolo
D
D
Ornaghi
F
F
Vegetti
W
W
Ginelli
E
E
Marozzi
Anna
A
D000328:Adult; D000483:Alleles; D001483:Base Sequence; D004252:DNA Mutational Analysis; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D016649:Primary Ovarian Insufficiency / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000502:physiology*; D049951:X Chromosome Inactivation / Q000502:physiology
D051860:Fragile X Messenger Ribonucleoprotein 1; C497683:FMR1 protein, human