Human Reproduction, Vol. 15, No. 1, 197-202,
January 2000
© 2000 European Society of Human Reproduction and Embryology
Association between idiopathic premature ovarian failure and fragile X premutation
1 Department of Biology and Genetics for Medical Sciences, University of Milan, Via Viotti 3/5, 20133 Milan, 2 First Department of Obstetrics and Gynaecology, University of Milan, 3 Department of Clinical and Biological Sciences, Ospedale di Circolo, Varese, and 4 Obstetrics and Gynaecology Unit, Department of Clinical and Biological Sciences, University of Insubria, Varese, and 5 Faculty of Medicine, Ospedale San Gerardo, University of Milan-Bicocca, Monza, Italy
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Abstract |
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A total of 106 women affected by premature ovarian failure (POF) were evaluated for fragile X (FRAXA) premutation. The POF patients were classified as having a familial condition (33 women), at least one relative with early menopause (12 women), or a sporadic condition (61 women). The FRAXA premutation was only detected in patients with familial (four out of 33) or sporadic POF (two out of 61). In general, the results obtained indicated that the prevalence [six out of 106, 6%, 95% confidence interval (CI) 3–11%] of FRAXA premutation is significantly higher in women affected by POF than expected (P = 1.24x10–3), suggesting a phenotype consequence of the premutation alleles. This relationship is more convincingly derived from the observation in two analysed pedigrees of a co-segregation between FRAXA and POF. These findings suggest a possible involvement of premutated alleles in ovarian failure, and indicate the utility of POF families screening for FRAXA premutation in order to prevent the transmission of mental retardation syndrome.
Key words: CGG expansion/FMR1 gene/fragile X syndrome/FRAXA premutation/premature ovarian failure
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Fragile X syndrome (FRAXA) is an X-linked dominant condition with incomplete penetrance (Fu et al., 1991
). The molecular basis of the disease is the expansion of a CGG trinucleotide repeat in the 5' untranslated region (UTR) of the FMR1 gene located at Xq27.3 (Verkerk et al., 1990; Warren and Ashley, 1995). In the normal population the CGG-repeat size is highly polymorphic (ranging from six to 54 repeats) and usually stably inherited (Fu et al., 1991); in carriers, the size of the repeated tract is between 60 and 200 repeats. This condition is termed premutation, since premutated alleles are susceptible to expansion when passed from a carrier to offspring. An expansion of more than 200 repeats (called full mutation) causes the hypermethylation of the CpG island upstream of the FMR1 gene and, consequently, its transcriptional inactivation (Pieretti et al., 1991; McConkie-Rosell et al., 1993). This molecular defect is the basis of the fragile X syndrome.
No obvious clinical symptoms of FRAXA syndrome occur in the premutated carriers, though a number of reports suggest that premutated alleles are associated with premature ovarian failure (POF), and several studies have indicated a relatively higher frequency of POF among FRAXA carriers than in the general population (Cronister et al., 1991; Schwartz et al., 1994; Partington et al., 1996). Moreover, a very recent multicentre study has shown that 16% of 395 women carrying FRAXA premutated alleles entered the menopause before the age of 40 years (Allingham-Hawkins et al., 1999). POF (Mendelian inheritance no. in Man 311360) is defined as the cessation of ovarian function before the age of 40 years, and it occurs in ~1% of women (Coulam et al., 1986). Ovarian dysfunction may be secondary to autoimmune disorders, infections, iatrogenic exposure or genetic disorders (Mattison et al., 1984; Alper et al., 1986; Conway, 1997; Anasti, 1998), and a number of authors have reported a familial transmission of POF characterized by a dominant or X-linked pattern of inheritance in patients with normal karyotype (Coulam et al., 1983; Mattisonet al., 1984; Vegetti et al., 1998; Bondy et al., 1998; Christin-Maitre et al., 1998). A significant association between FRAXA premutation and POF was derived both by the analysis of women carrying the premutated allele (Cronister et al. 1991; Allingham-Hawkins et al. 1999), and by the screening of women affected by POF. In this case, two out of 122 sporadic POF and five out of 26 familial POF showed fragile X premutation (Conway et al., 1995; Vianna-Morgante et al., 1996; Conway et al., 1998; Murray et al., 1998). Moreover, in a recent survey including 108 subjects with POF, 6.5% of women were found to carry the FRAXA premutation (Uzielli et al., 1999). Conversely, no FRAXA premutation was found in an analysis of 17 women with a family history of POF, and in 16 sporadic POF (Kenneson et al., 1997). Furthermore, in a preliminary investigation we did not find any evidence of prevalence of FRAXA premutation in POF women by analysing 22 familial conditions (Marozzi et al., 1999).
Since the contradictory results obtained by analysing the FRAXA prevalence in POF women could be due to the evaluation of limited series, we set out to expand our survey of POF patients by analysing further 11 familial and 61 sporadic POF manifestations.
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Materials and methods |
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A total of 106 patients affected by POF were recruited by the Reproductive Endocrinology Service of the Departments of Obstetrics and Gynaecology in Milan and Varese. In the present study, POF status is defined as the cessation of ovarian function for a period of >6 months before or at the age of 40 years, and is associated with a high concentration of follicle stimulating hormone (FSH) >40 IU/l, detected on two different occasions. All of the patients were recruited between May 1996 and February 1999 during a population study regarding clinical and genetic features of POF patients. Part of this survey has been reported previously (Vegetti et al., 1998
). All patients gave their informed consent to a check of their medical history and FRAXA status. Of the 106 POF patients, 45 had a family history of premature menopause with at least one relative experiencing POF (n = 33) or early menopause (n = 12). The early menopause condition is defined as the occurrence of menopause before the age of 45 years. This group of patients included 29 previously reported cases of POF (22 with POF relatives, and seven with relatives who had undergone an early menopause) (Marozzi et al., 1999). The remaining 61 patients were classified as having sporadic POF on the basis of their pedigree. All of the patients included in the study were phenotypically normal, and considered idiopathic because they did not show any POF-related conditions (ovarian surgery, previous chemo- or radiotherapy, autoimmune diseases, or genetic disorders). Two of the POF patients respectively had a son and a nephew with fragile X syndrome. The two patients did not know their carrier status prior to entering the study, and thus they have been included exclusively because of POF condition. Chromosome analysis based on high-resolution banding technique did not reveal any structural or numerical anomalies in any of the selected patients. Cytogenetic expression of the FRAXA fragile site was negative in all of the analysed patients.
DNA was extracted from whole blood by means of the proteinase K method as previously described (Marozzi et al., 1999). For the screening of FRAXA premutations genomic DNA was digested with EcoRI and EcoRI/EagI respectively, blotted onto Hybond N+ (Amersham, Italy) and hybridized to the Stb 12.3 probe as previously described (Rousseau et al., 1991).
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Results |
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We considered three groups of POF patients: the first with familial POF (33 patients; group A), the second with at least one relative affected by early menopause (12 patients; group B), and the third with a sporadic occurrence of the disease (61 patients; group C). The clinical features of the analysed patients with familial POF transmission are shown in Table I
; Table II shows the clinical features of the POF patients having at least one relative with early menopause.
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The 33 patients belonging to group A, and the 12 patients belonging to group B had a mean age at menopause of respectively 34.5 ± 5.9 (range 18–40), and 34.6 ± 4.5 years (range 26–40). The maternal age at menopause in groups A and B was 42.7 ± 6.9 (range 25–55) and of 43.6 ± 2.5 years (range 41–50) respectively. Among the patients with familial POF transmission the inheritance was maternal in 21 and paternal in eight patients. Three pedigrees showed both maternal and paternal POF transmission (Table I
). Moreover, 10 of the 12 POF patients belonging to group B had a mother with early menopause. The sporadic group included 61 POF patients, whose mean age at menopause was 31.8 ± 7.8 years (range 12–40); the mean age at maternal menopause was 49.5 ± 2.4 years (range 45–55).
Among the 33 pedigrees showing familial POF transmission (group A), four probands were found to have FRAXA premutation (four out of 33; 12%), and two FRAXA premutations were detected in the sporadic POF group (two out of 61; 3%). No FRAXA premutation was identified in the 12 POF with at least one relative with early menopause. The results obtained indicate a higher prevalence of FRAXA premutation in the studied POF population (six out of 106, 6%, 95% CI 3–11%) (Fisher's exact test, P = 1.24x10–3) than expected by evaluating a general Caucasian population (1:317) (Crawford et al., 1999). Conversely, the prevalence of FRAXA premutation in sporadic cases (3%) compared with the controls (1:317) (Crawford et al., 1999), or to the familial cases (12%) was not significantly different (Fisher's exact test, P = 0.069 and P = 0.17 respectively). On the other hand, the frequency of familial POF probands carrying the FRAXA premutation was greatly in excess than expected (1:317) (Crawford et al., 1999) (Fisher's exact test, P = 3.11x10–4).
All the pedigrees are shown in Figure 1; one pedigree of familial POF (Figure 1D; patient number 51 of Table I) was previously reported (Marozzi et al., 1999). In pedigrees A and C all of the family members experiencing POF at 25 (Figure 1A, I1), 38 (Figure 1C, I6) and 22 years (Figure 1C, II3) respectively, were also found to carry a FRAXA premutation. Regarding pedigree B, this analysis was not carried out because the POF relatives (Figure 1B, I2 and III4) were not available. Considering the four cases of familial POF transmission, in one pedigree (Figure 1D) the inheritance of the POF was paternal, whereas in pedigrees A–C the inheritance was maternal.
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p = estimated size of CGG repeat expansion. Neg. = negative for FRAXA premutation. The arrows indicate the probands. |
Discussion |
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A preliminary investigation on 29 POF women did not provide any evidence regarding an association between premature menopause and FRAXA premutation (Marozzi et al., 1999
). Since this result was probably caused by the small number of patients, we decided to extend our study, and here we report the results of an investigation carried out on 106 phenotypically normal women with POF. The total number of POF women carrying FRAXA premutation (six out of 106, 6%, 95% CI 3–11%) derived by our study differs significantly from population estimates carried out to evaluate the frequency of FRAXA premutation (Rousseau et al., 1995; Crawford et al., 1999). In particular, four fragile X carriers were identified in the POF familial group with at least one POF relative (33 probands), and two in the sporadic POF group (61 probands). No FRAXA carriers were identified among the POF women (12 probands) with at least one relative with early menopause.
The observed prevalence of two out of 61 (3%) of sporadic POF patients carrying a FRAXA premutation was not statistically significant. This result differs from those previously reported (Conway et al., 1998; Murray et al., 1998), but it could be explained by the limited dimension of our sporadic POF population. Conversely, the frequency of fragile X carriers among the familial POF probands was highly significant, thus indicating a preferential association between FRAXA premutation and POF in familial respect to sporadic condition. This result is in agreement with previous findings from the analysis of 25 familial POF (Conway et al., 1998; Murray et al., 1998).
Considering the pattern of transmission of POF and FRAXA premutation, in pedigrees A and C the probands inherited both conditions from the mother. In pedigree B, this was not investigated due to the unavailability of the POF mother. Conversely, in our previous reported familial POF, the observed FRAXA premutation was considered a post-zygote event, because the proband was assumed to be a mosaic for the premutation (Marozzi et al., 1999). An alternative explanation could be that the proband is not a mosaic, and she has inherited the FRAXA premutation from the father as the POF condition (Figure 1D).
The results obtained by studying familial POF indicate that at least in two pedigrees POF and FRAXA premutation are inherited in association. In fact, in these families, all the relatives affected by POF were also carriers of the FRAXA premutation. In particular, both the mothers of families A (I1) and C (I6), and one sister of the proband in family C (II3) were FRAXA carriers, and experienced menopause at the ages of 25, 38 and 22 years, respectively. On the contrary, the sisters of the probands in families A (II1) and C (II4) did not show either POF condition, and/or FRAXA premutation.
Families shown to have POF condition may therefore be considered at risk of carrying the FRAXA premutation. Thus, screening for FRAXA premutation in women with a familial condition of POF may be used to prevent the transmission of mental retardation syndrome by the relatives. One example of this situation can be derived from the analysis of pedigree C (Figure 1). The sister (II3) of the proband was affected by hypergonadotrophic oligomenorrhoea and after an ovarian stimulation programme she gave birth to a child affected by fragile X syndrome. In relation to this, she was found to be a FRAXA carrier and, 2 years later (at the age of 22 years), she underwent premature menopause. Moreover, as can be derived from pedigree A, the FRAXA analysis carried out on the 17 year old daughter of the proband has excluded the FRAXA premutation and, presumably, the risk of developing POF.
The analysis of pedigrees A and C also provides some evidence regarding the high rate of dizygous twinning (DZ) and the tendency to manifest early menopause by fragile X carriers. In this regard, the two probands in families A and C respectively have a male (Figure 1A, II2) and a female (Figure 1C, II4) dizygous twin, both negative for FRAXA premutation. Furthermore, the female (Figure 1C, II4) was not affected by POF; both the mothers (Figure 1A, I1 and Figure 1C, I6) experienced the POF, and were FRAXA carriers. It would therefore seem that FRAXA premutation might induce, as early signs of POF, elevated concentrations of FSH, and thus multiple ovulation (Braat et al., 1999; Vianna-Morgante, 1999).
The molecular mechanism, if any, underlying the link between FRAXA premutation and POF is at present unknown. A possible involvement of the FMR1 gene product in the pathogenesis of POF can be ruled out on the basis of several observations. Firstly, the premutation expansion of CGG at the 5' UTR of the FMR1 gene does not impair translation (Feng et al., 1995a). Secondly, though FMR1 gene expression is restricted to ovary, brain and testis and its primary transcript undergoes alternative splicing, no preferential spliced forms can be demonstrated in the ovary (Hinds et al., 1993; Verkerk et al., 1993; Khandjian et al., 1995). Thirdly, women carrying the full mutation, which causes the hypermethylation of the FMR1 gene promoter (Feng et al., 1995b) and the inhibition of translation, do not experience POF (Allingham-Hawkins et al., 1999). On the other hand, the co-segregation of FRAXA premutation and POF reported in this and in previous papers (Conway et al., 1995; Vianna-Morgante et al., 1996; Conway et al., 1998; Murray et al., 1998) might indicate either that the CGG premutated expansion has an effect on chromosomal regions responsible for POF, or that POF and FRAXA loci are in a linkage disequilibrium. The latter interpretation agrees with the mapping of the FMR1 gene and of a POF locus (POF1) in Xq27.3, and Xq26.1-q27 respectively (Krauss et al., 1987; Tharapel et al., 1993; Powell et al., 1994; Davison et al., 1998). However, the hypothesis of a linkage disequilibrium between the premutated CGG expansion and a nearby mutant allele responsible for the ovarian dysfunction is difficult to reconcile with the observation that women heterozygous for the full mutation do not show a prevalence of the POF condition. Conversely, an involvement in POF manifestation of the trinucleotide repeat in the range of 60–200 units could be postulated. In this regard, a role could be played by recently reported CGG-binding proteins (Deissler et al., 1996). In analogy to what was found by analysing another trinucleotide repeat disease, the Myotonic Distrophy (Philips et al., 1998), the premutated CGG repeated region could result in an alteration of the binding protein affinity (gain of function), producing a yet unknown deleterious molecular effect in the ovary. However, more research is necessary to understand the exact molecular mechanisms that in the ovary is at the basis of the premature menopause.
In conclusion, this study indicates an association between POF and FRAXA premutation, and suggests that screening of familial POF for FRAXA premutation will be useful to prevent the transmission of Fragile X syndrome.
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Acknowledgments |
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This work was supported by grant 93/G/T28, from the Istituto Superiore di Sanità, Rome, Italy
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Notes |
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6 To whom correspondence should be addressed
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Submitted on August 6, 1999; accepted on October 12, 1999.
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W. Sereepapong, P. Chotnopparatpattara, S. Taneepanichskul, R. Markham, P. Russell, and I. S. Fraser Endometrial progesterone and estrogen receptors and bleeding disturbances in depot medroxyprogesterone acetate users Hum. Reprod., March 1, 2004; 19(3): 547 - 552. [Abstract] [Full Text] [PDF]
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K. Gersak, H. Meden-Vrtovec, and B. Peterlin Fragile X premutation in women with sporadic premature ovarian failure in Slovenia Hum. Reprod., August 1, 2003; 18(8): 1637 - 1640. [Abstract] [Full Text] [PDF]
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P. Platteau, K. Sermon, S. Seneca, A. Van Steirteghem, P. Devroey, and I. Liebaers Preimplantation genetic diagnosis for fragile Xa syndrome: difficult but not impossible Hum. Reprod., November 1, 2002; 17(11): 2807 - 2812. [Abstract] [Full Text] [PDF]
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M. Hickey and I.S. Fraser Surface vascularization and endometrial appearance in women with menorrhagia or using levonorgestrel contraceptive implants. Implications for the mechanisms of breakthrough bleeding Hum. Reprod., September 1, 2002; 17(9): 2428 - 2434. [Abstract] [Full Text] [PDF]
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 D. M. Martin, G. Cassidy, F. Ahmad, and M. S. Martin Women with Learning Disabilities and the Menopause J Intellect Disabil., June 1, 2001; 5(2): 121 - 132. [Abstract] [PDF]
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R. D.L. Hundscheid, D. D.M. Braat, L. A.L.M. Kiemeney, A. P.T. Smits, and C. M.G. Thomas Increased serum FSH in female fragile X premutation carriers with either regular menstrual cycles or on oral contraceptives Hum. Reprod., March 1, 2001; 16(3): 457 - 462. [Abstract] [Full Text] [PDF]
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D. F. Rychlik Regarding recall bias in the association between idiopathic premature ovarian failure and fragile X premutation Hum. Reprod., August 1, 2000; 15(8): 1874 - 1874. [Full Text] [PDF]
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A. Marozzi Hum. Reprod., August 1, 2000; 15(8): 1874 - 1875. [Full Text] [PDF]
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