Reply to the Letters from Murray et al. and Vianna-Morgante and Costa

Hundscheid, Rubin D.L.; Thomas, Chris M.G.; Braat, D.D.M.; Oostra, Ben A.; Smits, A.P.T.

doi:10.1086/302967

Cited by 6 publications

(2 citation statements)

References 3 publications

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“…In this case, the POF phenotype is manifest only if the premutation is transmitted by the father. 68,69 However two other groups have not found parent of origin differences between carriers who have POF and those who do not and demonstrate that POF can result from both male and female transmission. 70,71 There may be differences in the populations studied by the three groups, but more work is needed to clarify any possible imprinting effect.…”

Section: Possible Mechanismsmentioning

confidence: 97%

Premature Ovarian Failure and the FMR1 Gene

Murray¹

2000

Semin Reprod Med

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FMR1 is an X-linked gene that codes for an RNA binding protein. Expansion of a triplet repeat within exon 1 of the gene causes the fragile X syndrome, which is characterized by mental retardation and various physical anomalies. The triplet repeat in FMR1 can expand to varying degrees. Only the very large expansions in which there is concomitant methylation of the gene cause the fragile X syndrome. Expansions of between 50 and 200 repeats are premutations. Although premutations were originally perceived to be without phenotypic effect, there is now substantial evidence that female carriers of premutations are at increased risk of having early menopause. The FMR1 premutation is also associated with a significant number of cases ascertained because of idiopathic premature ovarian failure, particularly when ovarian failure is a familial trait. The molecular mechanism to explain the association between ovarian failure and premutations is unknown.

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Section: Possible Mechanismsmentioning

confidence: 97%

Premature Ovarian Failure and the FMR1 Gene

Murray¹

2000

Semin Reprod Med

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“…These data were not confirmed by other groups, and additional data may be necessary to decide definitively about this intriguing hypothesis that would explain some of the characteristics of the association between POF and FRAXA premutation. [29][30][31] Two questions remain unanswered. The first derives from the low percentage of FRAXA premuta-tion carriers who develop POF and will require identifying the other risk factors involved.…”

Section: Fraxa Expansionmentioning

confidence: 99%

X Chromosome Genes and Premature Ovarian Failure

Bione

Toniolo

2000

Semin Reprod Med

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Premature ovarian failure (POF) is a disorder characterized by lack of ovulation and elevated levels of serum gonadotropins before the age of 40. The etiology of POF is not known but different environmental and genetic factors are involved, suggesting high heterogeneity of the disorder. The involvement of X-linked genes in the etiology of POF was hypothesized on the basis of its frequent association with chromosomal rearrangements and monosomies. In recent years a number of genes were described. Two genes, FRAXA and POF1B, have been formally demonstrated to be responsible for POF. Other genes have been proposed as candidates, but their role remains to be demonstrated.

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Premature ovarian failure in the fragile X syndrome

2000

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The full mutation leading to the fragile X syndrome is a dynamic trinucleotide repeat located in the 5' untranslated region of the FMR1 gene. The premutation allele contains approximately 60 to 199 repeats, is unstable, and originally not considered detrimental; that is, there did not appear to be a phenotype consequence of the long repeat tract. However, in the late 1980s and early 1990s, preliminary findings suggested that nonimpaired heterozygotes were at risk of early menopause and increased rates of twinning, both indications of ovarian failure. Once premutation carriers could be distinguished from full mutation carriers, this phenotype was found to be restricted to premutation carriers only. Based on the recent studies reviewed here, approximately 21% of premutation carriers have premature ovarian failure (POF) compared to only 1% in the general population, or a relative risk of 21. Moreover, among women with idiopathic sporadic or the more rare form of familial POF, approximately 2% and 14%, respectively, carry the premutation. To date, data supporting increased twinning rates are conflicting and need to be resolved. Neither the underlying cellular pathophysiology of POF caused by the premutation allele nor molecular mechanism underlying the presence of the long repeat tract of the premutation allele is understood. Irrespective, women who carry the premutation allele should have not only genetic counseling but also fertility counseling to ensure that they reach their goals for reproduction.

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Reply to the Letters from Murray et al. and Vianna-Morgante and Costa

Abstract: Imprinting effect in premature ovarian failure confined to paternally inherited fragile X premutations. Am J Hum Genet 66:413-418 Morton NE, Macpherson JN (1992) Population genetics of the fragile-X syndrome: multiallelic model for the FMR1 locus.

Cited by 6 publications

References 3 publications

Premature Ovarian Failure and the FMR1 Gene

Premature Ovarian Failure and the FMR1 Gene

X Chromosome Genes and Premature Ovarian Failure

Premature ovarian failure in the fragile X syndrome

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