Hum. Reprod. Advance Access published online on December 16, 2005
Human Reproduction, doi:10.1093/humrep/dei432
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1 Department of Biology and Genetics for Medical Sciences, University of Milan, Milan
* To whom correspondence should be addressed. BACKGROUND: Studies attempting to precisely define the range of fragile mental retardation 1 (FMR1) expansions and its influence 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. RESULTS AND CONCLUSION: 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.
Received July 29, 2005
Revised September 30, 2005
Accepted November 21, 2005
Article
Influence of intermediate and uninterrupted FMR1 CGG expansions in premature ovarian failure manifestation
B. Bodega 1,
S. Bione 2,
L. Dalprà 3,
D. Toniolo 4,
F. Ornaghi 1,
W. Vegetti 5,
E. Ginelli 1,
and
Anna Marozzi 1 *
2 Institute of Molecular Genetics-CNR, Pavia
3 Department of Experimental and Environmental Medicine and Medical Biotechnology, University of Milan-Bicocca, Monza
4 Dibit-San Raffaele Scientific Institute, Milan
5 Department of Obstetrics and Gynecology, University of Milan, Italy
Anna Marozzi, E-mail: anna.marozzi{at}unimi.it
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