X-linked premature ovarian failure: a complex disease Daniela Toniolo Involvement of the X chromosome in premature ovarian failure was demonstrated by the relatively frequent chromosomal rearrangements in patients, but the requirement of two X chromosomes for ovarian function was quite unexplained until recently. Review of the data on chromosomal rearrangements suggests that several genes along the X chromosomes contribute to ovarian function. In most instances, no single X chromosome gene has a causative role in premature ovarian failure, and the phenotype is likely to derive from the additive effect of X-linked and non-X-linked factors. Recent data on a small group of balanced X–autosome translocations showed that X-linked premature ovarian failure might also be caused by a different mechanism, namely position effect of the X chromosome on non-X-linked genes, and suggest a peculiar organization of the X chromosome during oogenesis. Addresses Department of Molecular Biology and Functional Genomics, Via Olgettina 58, 20132 Milano, Italy Corresponding author: Toniolo, Daniela (
[email protected])
Current Opinion in Genetics & Development 2006, 16:293–300 This review comes from a themed issue on Genetics of disease Edited by Andrea Ballabio, David Nelson and Steve Rozen Available online 2nd May 2006 0959-437X/$ – see front matter # 2006 Elsevier Ltd. All rights reserved. DOI 10.1016/j.gde.2006.04.005
Introduction Disorders of ovulation are common in human females and account for a large proportion of infertility problems. Premature ovarian failure (POF; Online Mendelian Inheritance in Man, [OMIM] 311360 and 300511) comprises a group of disorders defined by hypergonadotropic ovarian failure before 40 years of age [1,2]. POF affects 5– 10% of menopausal women and has a prevalence of about 1% in the general female population in Caucasian, Hispanic and African Americans [3]. The prevalence is lower in Japanese (0.14%) and Chinese (0.5%). POF results in infertility and lifelong sex steroid deficiency, and it is potentially associated with the severe health risks common to natural menopause, such as cardiovascular and neurological disorders, and osteoporosis. The etiology of POF is not known, but several mechanisms can be hypothesized, including a reduced oocyte or primordial follicle pool, accelerated follicular atresia, and alterations www.sciencedirect.com
in follicular recruitment or maturation. Known causes of POF include surgical intervention, radiation and chemotherapy. Environmental factors such as infection, stress and smoking have also been implicated in the disorder, and some patients have shown evidence of autoimmune etiology associated with the presence of anti-ovarian antibodies and other self-tissue antibodies [4,5]. A genetic basis for POF has been well established by the report of numerous familial cases. The identification of genes responsible for autosomal recessive [6], X-linked dominant [7] or autosomal dominant syndromic forms [8,9] of the disease demonstrated a monogenic component. POF was demonstrated in a fraction of women affected with galactosemia and autoimmune polyendocrinopathy– candidiasis–ectodermal dystrophy (APECED) or carrying the FMR1 gene premutation (see Glossary) [2,10], showing that mutations in those genes might represent risk factors for POF. Finally, isolated mutations were found in a few candidate genes, but they were never definitively confirmed by functional analysis or genetic replication [2]. In general, the genes identified still account for a small percentage of the POF cases, demonstrating that the disorder is genetically highly heterogeneous. A role for X chromosome genes was suggested by the frequent observation of X chromosomes anomalies in patients. In this review, I summarize the data from the original observations and describe the most recent results on the Xlinked factors involved in POF.
Turner syndrome and partial monosomies X chromosome monosomy or Turner syndrome is characterized by growth failure and infertility and is often associated with a characteristic cognitive deficit and a range of anatomic abnormalities, which are highly variable form one patient to another [11]. The pathogenesis is complex. It might be due in part to the non-specific effects of the aneuploidy, but the prevalence of most Turner syndrome traits among 45,X patients is far in excess of what would be expected if only aneuploidy was involved. The finding that several X-linked genes escape X chromosome inactivation suggests that the most likely explanation for the common phenotypic manifestations of Turner syndrome is the effect of monosomy for distinct genes [11]. This was the case for short stature and most of the skeletal features of Turner syndrome that are caused by haploinsufficiency for the SHOX gene, in the pseudoautosomal region in Xp [12–15] (See also review by RJ Blaschke and G Rappold, this issue [16]). Infertility in 45,X patients is caused by oocyte-loss in the early stages of the meiotic prophase, before the pachytene Current Opinion in Genetics & Development 2006, 16:293–300
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Glossary CpG island: Non-methylated GC- and CpG-rich regions; usually they embed the 50 end and promoter regions of housekeeping genes. Position effect: Deletion of cis-regulatory domains localized at a distance outside a transcription unit, or translocation of cisregulatory elements to different position on the genome might cause changes in gene regulation that have been demonstrated mainly by the study of disease-associated chromosomal breaks. Chromosomal rearrangements can cause changes in chromatin conformation that can control protein access and regulate transcription. Disruption of these finely tuned mechanisms can cause disease. Premutation: A mutation that confers risk to further mutation. It is found in genes containing trinucleotide repeats that can expand to larger repeat number and cause disease. Examples include the FMR1 gene, the myogenic dystrophy gene and many others causing mainly neurological disorders. Preproregion: Translated regions that have to be removed for protein activation.
meiotic stage, resulting in ovarian dysgenesis and streak ovaries [17]. Ogata and Matsuo [18] argued that ovarian failure in X monosomies could be caused by non-specific pairing errors at meiosis that increase the probability of germ cell atresia — the extent of ovarian failure correlates with the extent of pairing failure [18]. Genotyping partial X chromosome monosomies in women presenting the full Turner syndrome phenotype or only ovarian failure highlighted specific regions that might be involved in ovarian function; furthermore, these studies seemed to favor haploinsufficiency for specific Xq or Xp genes as the cause of POF [19]. All Xp deletions excluded most of the p arm and highlight the involvement of the proximal part of Xp in ovarian function [20–22]. A locus was defined at Xp11.2–q22.1, within which mapped several of the Turner syndrome traits, including ovarian failure [20]. Xq terminal deletions were relatively common and frequently very large [19]. They were associated almost exclusively with secondary or primary amenorrhea and only rarely with other Turner traits [18,23,24]. Larger deletions presented primary amenorrhea, whereas in deletions originating in Xq21 or further distally the more common phenotype was secondary amenorrhea. In women with normal fertility, a number of interstitial deletions in proximal Xq excluded most of the proximal part of Xq, from Xq21 to the centromere [25]. One family with several affected women and a few isolated cases of POF presented deletions in the middle of the long arm, spanning Xq22–q26 (these are cases III-5, L.L. and GM09332 in Figure 1) [24,26,27]). Smaller deletions were reported with breakpoints from Xq26–q27 [28,29,30–32]; some were terminal deletions, others included the Xq telomere and part of Xq28. Deletion mapping of the better-characterized cases defined a 4 Mb locus for POF in Xq27–q28, and a larger locus in the middle of Xq (Figure 1). Current Opinion in Genetics & Development 2006, 16:293–300
The phenotypes of women carrying the smallest deletions within Xq27–q28 were variable [28,29,30–32]. Some of the carriers had early menopause — between 40 and 45 years of age — and numerous children. Some had irregular menstruation and secondary amenorrhea. One case had primary amenorrhea. In a few instances, deletions were found in families and segregated with different temporal onset of ovarian failure. In two cases, the extent of the deletions were defined in several affected members of the family and were found to be identical [30,32]. This observation, together with the relatively small number of interstitial deletions in comparison with the large Xq or Xp deletions, suggested that relatively small deletions, which involve fewer genes, might not cause a severe phenotype and/or require additional non-X-linked factors. In conclusion, deletion mapping seems to favor haploinsufficiency for several Xlinked genes along the X chromosome as the mechanism responsible for ovarian failure. Given that both X chromosomes are active in the oocytes from the onset of meiosis, many loci for which a double dose is required for ovarian function could be present on the X chromosome [33]. Alternatively, it is intriguing to think that escape from X chromosome inactivation could have been maintained during X chromosome evolution in the somatic cells of the ovarian follicles, as a sex-specific mechanism important for follicular maturation and ovulation.
The critical region in Xq Cytogenetic analysis of POF patients showed that, in addition, balanced X–autosome translocations could be associated with POF and defined a ‘critical region’ for normal ovarian function on the long arm of the chromosome, corresponding to the Xq13.3–q27 interval, which is often divided into two portions, Xq13–q21 and Xq23–q27 [34,35]. Alternative explanations for the phenotype were proposed that could account for the size of the critical region: they ranged form the presence of loci along Xq that could be disrupted by the chromosomal rearrangements to a ‘position effect’ (see Glossary) caused by the rearrangements on flanking genes. A direct effect of the rearrangements was also suggested, because the presence of unsynapsed regions might be recognized by meiotic check-points or other checkpoints that act during ovarian follicle maturation and that might increase apoptosis and reduce the number of ovarian follicles, thereby leading to POF [36,37]. Molecular definition of the POF critical region by fluorescent in situ hybridization mapping of balanced X–autosome translocations supported the cytogenetic results and the extension of the POF critical region over >50 Mb of the X chromosome long arm, distal to XIST [27,38–40]. A search for genes interrupted by the breakpoints in balanced X–autosome translocations identified five genes interrupted by the translocations, out of >40 balanced www.sciencedirect.com
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Figure 1
The POF critical region and chromosomal rearrangements in Xq. (a) Schematic representation of the region. Vertical lines indicate the positions of the X–autosome balanced-translocation breakpoints mapped by different laboratories. The normal cases are in italics. (b) Schematic gene map (from http://www.ensembl.org/) demonstrating gene frequency variations along Xq. Representative interstitial deletions and small terminal deletions involving Xq27–q28 described in the text are shown as horizontal bars; dotted regions indicate map intervals. Above are the normal cases (no POF), below are the POF associated cases (POF). POF critical region I is shown as a blue area. The two minimal deleted regions in Xq are shown as pink areas.
translocations mapped. The DIAPH2 gene, which lies in proximal Xq22 and is interrupted in a familial case of POF, is one of the human homologues of the Drosophila melanogaster dia (diaphanous) gene, which affects female fruit fly fertility by interfering with the cell division of ovarian follicular cells and germ cells [41]. Despite the functional similarity with dia, the relevance of DIAPH2 in the etiology of POF is not known, nor that of the XPNPEP2 gene, which is in Xq25 [42]. On the other end, mutation and expression analysis failed to demonstrate a role in POF for the other three genes interrupted by translocations, POF1B, DACH2 [43] and CHM [44], confirming that X-linked gene interruption is not a common cause of POF in this group of patients. Breakpoint mapping in POF patients and in normal women showed that the majority of the X chromosome breakpoints were mapped either to genomic regions free of transcribed sequences or to ‘gene deserts’, and confirmed that mechanisms different from gene interruption www.sciencedirect.com
might be responsible for X-linked POF [27,39,42]. The extensive analysis by Rizzolio et al. [27] revealed that translocations in non-POF women were interspersed with and mapped within a few hundred kilobases of POFassociated breakpoints. This finding has definitively eliminated chromosomal translocations or the presence of unsynapsed chromosomal regions per se from being responsible for the ovarian disorder. The most striking observation was that 80% of the X chromosome breakpoints associated with POF interrupted Xq21, a region of the X chromosome in which large interstitial deletions were identified in women that apparently either did not have conceiving problems or were affected by a very mild form of POF (Figure 1). In the same study, gene expression and RNA in situ hybridization analysis of the genes flanking a cluster of 10 breakpoints in Xq21 showed that none of the X-linked genes from a 2 Mb region were highly expressed in the adult ovary nor had an ovarian follicle- or oocyte-specific expression pattern. Thus, the most likely explanation of the balanced translocations Current Opinion in Genetics & Development 2006, 16:293–300
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phenotype is that interruption of Xq21 might have a position effect on autosomal genes translocated to the X chromosome; from this, it should be expected that ovary-specific genes would be found at the autosomal breakpoints: the authors state to have preliminary data indicating that this is the case. The demonstrated complete overlap of the two groups of rearrangements in Xq21, together with their different affect on gonadal function, showed that alteration of the critical region can cause POF through mechanisms different from monosomy for genes in Xq21, as occurs in Turner Syndrome and partial X-monosomies. These observations also indicate that the two portions of the POF critical region, previously defined by cytogenetics, might indeed be functionally different and, therefore, should be defined as critical regions I and II (Figure 1). POF involving critical region II (i.e. when partial monosomies are associated with POF) could be a result of a position effect of the breakpoints causing haploinsufficiency of X-linked genes by alteration of long-distance enhancers, as has been shown for other cytogenetic rearrangements [45].
high levels throughout the course of follicular maturation and ovulation [51,52]. Mutations in Gdf9 and Bmp15 were identified in mouse and sheep strains showing altered ovulation [51,53]. In humans, BMP15 was reported to carry causative mutations in two sisters who were affected with primary amenorrhea and who carried a mutation inherited from the father [7]. The mutation caused substitution of a conserved amino acid in the preproregion (see Glossary) of the protein [7]. As in all TGF-b family members, processing of the precursor is a critical step; accordingly, the human mutation was shown to act as dominant negative and to decrease in vitro growth of granulosa cells after stimulation with wild type BMP15. In humans, BMP15 maps to Xp11.22, proximal to but not within the Turner syndrome candidate region defined by deletion analysis [20]. Accordingly, its presumed role in ovarian function seems to be more relevant for follicular maturation or in determining the ovulation quota than for establishing the final number of ovarian follicles as is expected to occur in Turner syndrome [54]. No other mutations in BMP15 were reported, and its prevalence in POF is not known.
FMR1 premutation The size of the POF critical region II (>15 Mb) and the lack of candidate genes within it suggest that different mechanism(s) might be involved. In Drosophila, genes that have been mislocalized next to heterochromatin by chromosomal rearrangements or transposition are transcriptionally silenced. They acquire a heterochromaticlike appearance in polytene chromosomes, and significant changes occur in their higher-order chromatin structure [46,47]. A similar phenomenon might occur if autosomal genes are translocated to the POF critical region I, suggesting that this part of the X chromosome plays a novel role during oogenesis that needs to be clarified.
The X chromosome and genes for POF Identification of the X chromosome POF candidate regions have implicated an involvement for several Xlinked genes in the POF phenotype. Only two X-linked genes for ovarian failure were definitively demonstrated, BMP15 (BONE MORPHOGENIC PROTEIN 15) and the premutated allele of the FMR1 (FRAGILE X MENTAL RETARDATION 1) gene.
BMP15 BMP15 is a member of the large super-family of the transforming growth factor b (TGFb) proteins, involved in diverse cellular processes during embryonic development and tissue formation [48,49]. Many members of the family (e.g. inhibins and activins, Mu¨llerian-inhibiting substance and GDF9 [growth differentiation factor 9]) have been implicated in mammalian reproduction [50]. Studies in the mouse showed that both Bmp15 and Gdf9 are specifically expressed in the oocyte; this expression begins in the one-layer primary oocyte and remains at Current Opinion in Genetics & Development 2006, 16:293–300
To date, the FMR1 premutation, which represents a risk factor for POF, is the most common of the known causes of POF. The FMR1 gene, in Xq27, is responsible for Fragile X syndrome (see also review by K Garber et al., this issue [55]), a form of X-linked mental retardation associated with minor somatic traits [56–58]. Mental retardation in this case is caused a CGG trinucleotide in the 50 untranslated region (UTR) of the gene being expanded to more than 200 repeats (i.e. full mutation). Normal size alleles contain expansions ranging from 6 to 49 repeats. Alleles with expansions between 59 and 199 repeats might further expand to full mutation size within one generation [59]. Intermediate size alleles (50–59 repeats) are potentially unstable and might lead to full mutation in a few generations when transmitted; the instability increases with the larger alleles (by 19% for 49–54 repeats; by 30.9% for 55–59 repeats) and includes both expansion and contraction of the repeat size [59]. Owing to the ambiguity of determining the lower range of the premutation, and to the intrinsic inaccuracy of the methods for repeat-sizing, repeat lengths from 55 CGGs are defined as premutations, and the 45–54 CGG repeats, with the lowest probability of expansion, are defined as ‘gray zone’ mutations. As a consequence of the full mutation, the CpG island (see Glossary) surrounding the 50 UTR of the FMR1 gene becomes hypermethylated, the transcription is shut off and FMR1 protein is absent. In cells carrying the premutation alleles, the situation is quite different because FMR1 mRNA levels are elevated, and FMR1 is present [60–62]. FMR1 mRNA levels increase with increasing CGG repeat length within the premutation range, and www.sciencedirect.com
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FMRP levels decrease as a consequence of reduced translational efficiency of the premutated mRNA, starting with the FMR1 alleles in the gray-zone range [63,64]. Alternative transcription start sites might also be used, and the relative proportion varies with repeat length [65]. Premutation carriers, both females and males, were initially considered to be normal, and indeed they are not affected with mental retardation. They are, however, affected with unique disorders (e.g. POF, FXTAS (Fragile X-associated tremor–ataxia syndrome), a late-onset neurological disorder occurring mainly in males [66]).
that the etiology of POF is different from that of FXTAS or that specific mechanisms might act in the oocytes, turning off synthesis of the premutated mRNA at around 100 repeats. Various mechanisms can be proposed to explain the risk associated with these repeats: reduction of the methylation threshold; secondary structures that might mask the CGG repeats; the use of alternative start sites; or expansion to full mutation. Although the actual mechanism(s) are still unknown, they should also involve interaction with other as yet undetermined risk factors that are specific for oocyte or ovarian follicles.
Conclusions Soon after identification of the FMR1 gene, it was realized that normal carriers of the FMR1 mutation had a significantly higher frequency of POF [67]. Systematic studies of premutation- and full-mutation-carriers and of normal controls confirmed and estimated the relative risk for premutations carriers [68,69]. The premutation was subsequently found among women affected with idiopathic POF [70], and recent studies demonstrated a significant enrichment of intermediate size expansions (gray zone) among POF patients [71,72]. Since the original survey, several studies have revealed that 2 to 5% of idiopathic POF carry a premutated allele, and 13 to 15% of the women carrying the premutation in Fragile X syndrome families present with POF [73–75]. In all the studies, women carrying the full mutation or the normal sizerange alleles have the same risk (about 1%) of having POF as the general population. Family studies also showed that the FMR1 premutation might cause a wide range of ovarian dysfunctions, in addition to POF, because premutation carriers who were still cycling demonstrated increased levels of follicle-stimulating hormone (15 IU/l) compared with those of non-carriers and full mutation relatives, suggestive of a depleted ovarian reserve [76,77]. Accordingly, the average age of menopause occurred earlier for premutation carriers than for non-carriers [74,78]. In conclusion, expansion of the FMR1 CGG repeat from the normal size-range represents the most common of the known risk-factors that might cause ovarian dysfunction and eventually POF. Part of the risk depends on the FMR1 allele involved. In some families — but not all — skewed X chromosome inactivation could be correlated with POF. More significant is the association found with the CGG repeat size. In all studies, the risk increased with increasing length of the repeat, up to the 80 repeats threshold, when the risk of ovarian dysfunction reached its highest [71,72,79,80]. This is in agreement with a toxic effect of the premutated mRNA itself, which might sequester CGG binding proteins that are important for RNA processing. This model is similar to that proposed for the pathogenesis of myotonic dystrophy type 1 and for FXTAS [66,81]. However, the risk for POF appears to plateau and/or decrease with higher repeat number (100) [79,80], suggesting either www.sciencedirect.com
The involvement of the X chromosome in POF is well established. Given that most of the original evidence derived from quite diverse and rather large chromosome rearrangements, a generalized effect of the rearrangements on meiosis or on X chromosome inactivation was proposed [18,36]. No further evidence in this sense was provided, and most studies that precisely outlined the regions of the chromosome involved seemed to favor haploinsufficiency for specific genes as the cause of the ovarian disorder, because it was also the cause of short stature. However, recently published data on the critical region for ovarian failure appear to be compatible with a structural role for the X chromosome in some of the POF rearrangements. In this group of rearrangements, POF seems to be independent of the presence of X-linked genes and to result from a peculiar X chromosome organization that occurs during oogenesis and which might affect the expression of non-X-linked genes in the oocyte. The role of X-linked genes in the disorder is still poorly defined, and few genes have been identified. Moreover, both genes identified to date, BMP15 and FMR1, are not within the X chromosome candidate regions defined by deletion mapping. Thus, the data suggest that many Xlinked genes and other factors might be involved in ovulation, and that only a few could be responsible for the monosomy phenotype and Turner syndrome. Furthermore, haploinsufficiency for several X-linked genes or additional factors not necessarily involved in Turner syndrome might be required to cause POF, as shown both by the observation that large deletions are more common than small ones in POF patients and by the variable phenotypes of women carrying relatively small but identical deletions. These findings show that POF is mainly a polygenic disorder, as suggested by family studies [82] and in agreement with the analysis of the FMR1 premutation. Private mutations in a myriad of different genes might be involved in POF: mutation analysis of candidate genes in human patients, and the fact that a large number of ovary-expressed genes affect fertility in the mouse indicate that, indeed, mutations in many different genes could be able to reduce the oocyte pools and to produce infertility. However, it is not unlikely that common variants might be associated to the Current Opinion in Genetics & Development 2006, 16:293–300
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disorder and might represent a relevant portion of the risk in patients. POF is, in fact, a disorder whose relevance has recently increased with the increase of the average female reproductive age. DNA sequence variants altering genes involved in ovarian function could have been maintained during human evolution and could now be found associated with POF. If this is the case, studies of selected populations of the appropriate size should be carried out to show association and to identify the remaining risk factors. This approach might be more productive than the search for causative mutations in candidate genes in small populations, which, until recently, was the accepted method for most studies.
Acknowledgements I thank all the members of the laboratory that have participated in many discussions on X-linked POF over the years. A special thanks to Flavio Rizzolio and Silvia Bione, who have contributed most to our studies. Experiments from my laboratory were supported by MIUR-FIRB RBNE0189HM_005 and by Telethon, Italy.
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73. Uzielli ML, Guarducci S, Lapi E, Cecconi A, Ricci U, Ricotti G, Biondi C, Scarselli B, Vieri F, Scarnato P et al.: Premature ovarian failure (POF) and fragile X premutation females: from POF to to fragile X carrier identification, from fragile X carrier diagnosis to POF association data. Am J Med Genet 1999, 84:300-303. 74. Murray A, Ennis S, MacSwiney F, Webb J, Morton NE: Reproductive and menstrual history of females with fragile X expansions. Eur J Hum Genet 2000, 8:247-252. 75. Murray A: Premature ovarian failure and the FMR1 gene. Semin Reprod Med 2000, 18:59-66. 76. Murray A, Webb J, MacSwiney F, Shipley EL, Morton NE, Conway GS: Serum concentrations of follicle stimulating hormone may predict premature ovarian failure in FRAXA premutation women. Hum Reprod 1999, 14:1217-1218. 77. Hundscheid RD, Braat DD, Kiemeney LA, Smits AP, Thomas CM: Increased serum FSH in female fragile X premutation carriers with either regular menstrual cycles or on oral contraceptives. Hum Reprod 2001, 16:457-462. 78. Hundscheid RD, Sistermans EA, Thomas CM, Braat DD, Straatman H, Kiemeney LA, Oostra BA, Smits AP: Imprinting effect in premature ovarian failure confined to paternally inherited fragile X premutations. Am J Hum Genet 2000, 66:413-418. 79. Sullivan AK, Marcus M, Epstein MP, Allen EG, Anido AE, Paquin JJ, Yadav-Shah M, Sherman SL: Association of FMR1 repeat size with ovarian dysfunction. Hum Reprod 2005, 20:402-412. See annotation [80]. 80. Ennis S, Ward D, Murray A: Nonlinear association between CGG repeat number and age of menopause in FMR1 premutation carriers. Eur J Hum Genet 2006, 14:253-255. These two large and very important studies [79,80] establish correlations between characteristics of the FMR1 premutation and the risk of POF. Both studies demonstrate a non-linear association between menopausal age and premutation size, suggesting that individuals with premutations between 80 and 100 CGG repeats are at greatest risk of developing POF; the authors also show that larger premutations are at lower risk and propose several mechanisms that might explain the results. 81. Ebralidze A, Wang Y, Petkova V, Ebralidse K, Junghans RP: RNA leaching of transcription factors disrupts transcription in myotonic dystrophy. Science 2004, 303:383-387. 82. Vegetti W, Grazia Tibiletti M, Testa G, de Lauretis Y, Alagna F, Castoldi E, Taborelli M, Motta T, Bolis PF, Dalpra L et al.: Inheritance in idiopathic premature ovarian failure: analysis of 71 cases. Hum Reprod 1998, 13:1796-1800.
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