REVIEW URRENT C OPINION
Genetics of premature ovarian failure Ekrem M. Bilgin and Ertug Kovanci
Purpose of review To provide an overview on the genetic basis of premature ovarian failure (POF) with specific attention to recently published molecular genetic studies. Recent findings POF is an insidious cause of female infertility. Despite enormous efforts to understand the genetic pathogenesis, we know almost nothing but Turner syndrome and Fragile X syndrome. The era of genomewide association studies opened a new window into the understanding of the complex, polygenic nature of ovarian failure by identifying several candidate regions. Most of the genes in these regions are waiting for confirmation in isolated POF cohorts. Recently, molecular evidence on the regulatory role of small noncoding RNAs in folliculogenesis and oocyte development began to emerge. The association between certain microRNA polymorphisms and POF has been reported. Summary Although there exist numerous candidate genes in the literature, a few of them have comprehensive and consistent molecular workup that showed strong genotype/phenotype association. Keywords candidate genes, genetics, infertility, mutations, premature ovarian failure
INTRODUCTION Premature ovarian failure (POF) is a significant cause for female infertility. Natural cessation of menses is 51 years on average [1]. POF is defined as a cessation of menses before age of 40. The diagnosis is made based on increased gonadotropin levels (follicle stimulation hormone >20 IU/l). Leading clinical features are amenorrhea with hypoestrogenism [2] and its prevalence is one to three in 100 women by age 40 [3,4]. It is preceded by a gradual decline in ovarian function. Although there are some well known causes [X chromosome perturbations, Fragile X mental retardation 1 (FMR1) permutation], the majority of the POF cases are idiopathic. It appears that there is a strong genetic basis [5,6] for age at menopause as it is similar among first-degree relatives such as sister– sister and mother–daughter pairs [7]. POF is a complex condition which most likely has a polygenic nature. Defects in multiple genes cause ovarian failure in animal models. Both autosomal and sex chromosome perturbations are associated with POF in women. It is reasonable to begin with searching candidate genes in genetic pathways related to germ cell development. Many oocytespecific genes have been defined [e.g., growth differentiation factor 9 (GDF9), bone morphogenetic protein 15 (BMP15) and newborn ovary homeobox
(NOBOX)] by the help of animal studies and each plays a crucial role at key points during oocyte development. Studies on rare syndromes associated with POF (e.g., blepharophimosis, ptosis and epicanthus inversus syndrome and Perrault syndrome) have been helping us identify new candidate genes as well [8]. The genetic variations of basic reproductive hormones and their receptors [e.g., estrogen receptor, follicle stimulating hormone receptor (FSHR)] have always been promising, although the results are far from being explanatory in most cases. Recently, genome-wide association studies (GWAS) have provided us with several novel candidate regions and many more candidate genes [9,10]. In this article, we summarize the recently published data on candidate genes, genetic variants and made an effort to highlight a new perspective on genetics of POF. We also developed a grading system for all candidate genes (Table 1). Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA Correspondence to Ertug Kovanci, MD, Obstetrics and Gynecology, Baylor College of Medicine, 7900 Fannin Street, Suite 4400, Houston, TX 77054, USA. Tel: +1 713 512 7064; fax: +1 713 512 7829; e-mail: [email protected] Curr Opin Obstet Gynecol 2015, 27:167–174 DOI:10.1097/GCO.0000000000000177
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KEY POINTS GWAS are a valuable resource for identification of new candidate genes for POF. Regulatory role of small noncoding RNAs in folliculogenesis and oocyte development is becoming apparent. Novel approaches in the search of genetic mechanisms of POF are needed.
CHROMOSOMAL ABNORMALITIES This group is a well known cause of POF. Particularly, X chromosome abnormalities are estimated to constitute up to 13% of cases [11]. Main aberrations include monosomies, trisomies, translocations, deletions and copy number variants (CNVs) [2]. The numerous POF case reports have led to the identification of ‘critical regions’ on both the short and long arms of the X chromosome such as Xq13.3Xq27 and Xp13.1-p11. Autosomal chromosomal abnormalities and balanced translocations can also be associated with POF.
Turner syndrome Turner syndrome is observed with an incidence of one in 2500 female births that makes it the most common X chromosome abnormality leading to POF. Cytogenetically, mosaicism is frequent. The specific molecular pathways affecting ovarian
function in Turner syndrome patients are yet to be discovered. Germ cell atresia and the extent of ovarian failure vary based on the mosaicism level. In a recent study on X chromosome mosaicism, Castronovo et al. [12] concluded that 10% euploid cell line might lead to spontaneous menarche. Their cohort consisted of 40 women with Turner syndrome (six women with spontaneous menarche and 34 women with primary amenorrhea). By using array comparative genomic hybridization (aCGH) analysis and quantitative PCR confirmation, they identified CNVs that involved autosomal and X-linked ovary-related loci containing novel candidate genes (pregnancy-associated plasma protein A and phosphodiesterase 8A). They suggested gene dosage as a significant mechanism in ovarian phenotype of women with Turner syndrome.
Fragile X syndrome The gene associated with Fragile X syndrome is located on chromosome Xq27.3. This gene called FMR1 results in Fragile X syndrome if its trinucleotide (CGG) repeats are expanded over 200 (full mutation). On the contrary, premutation (55–199 CGG repeats) is associated with POF and subsequent infertility. However, women with the full mutation are not at risk for POF. In Caucasian women, 20–28% of carriers develop POF [13,14]. On the contrary, carrier status in women with POF was found to be ranging from 0.8 to 14% depending on the family history [15–17].
Table 1. Grading system for candidate genes Grade
Gene name
8
To be found
7
NOBOX
6
CDKN1B, CITED2, CPEB1, CSPG5, CXCL12, HFM1, MSH5, NANOS3, TGFBR3, FIGLA, GDF9
5
ALOX12, BRSK1, LAMC1, MCM8/MCM9, NLRP11, SYCP2L, TMEM150B
4
AIRE, ATM, BMPR1B, CLPP, FMR1/FMR2, FOXL2, GALT, GNAS, HARS2, HSD17B4, LARS2, NOG, PMM2, POU5F1, SHOX
3
ADAMTS19, ADAMTS16, AMHR2, BMP15, CYP17A1, DIAPH2, DMC1, DNAH6, EIF2B2/EIF2B4/EIF2B5, ESR1, FOXO1, FOXO3, GREM1, HK3, INHA/INHB, KDR, LHR, SF-1, MT-ATP6, POF1B, SALL4, SOHLH2, SMARCC1, SYCE1, TAF4B, TNFSF11, TSPYL6, USP9X, XIST, XPNPEP2, ZP1/ZP2/ZP3, ZFR2
2
ADAMTS1, AR, AKT1, AGTR2, ALOX15, BAX, BCL2, BDNF, CENPI, CX37/CX43, DACH2, DAZL, DMRT1, DLX5/DLX6, ESR2, FOXO4, FST, BRCA1/BRCA2, GPR3, H1FOO, KISS1, KIT, LATS1, LEP, LHX8, MATER, MTHFR, NGF, NXF5, PDK1, PIN1, POLG, PGRMC1, PTHB1, PTEN, RPS6, SKP2, SPO11, TSC1, YY1, VEGF, WNT4, WT1
1
CBX3, HS6ST1/HS6ST2, KISS1R, PDE3A, RFPL4, SMAD1/SMAD5, RHBDL2, PRIM1, UIMC1, EXO1, FNDC4, TLK1, METAP1D, HELQ, RNF44, BAT2, ASH2L, MPPED2, KPNA3, TDRD3, GSPT1, CLDN11, SLC44A4, GPR124, DYNC1H1, BANP, F5, CYP1B1, HSDB1, APOE, FAM175A, FANCI, IL11, HSD17B6
8, Strong candidate, supported by animal studies and/or functional studies and proven to be causative in majority of women in premature ovarian failure (POF) cohorts by direct sequencing; 7, strong candidate, supported by animal studies and/or functional studies and proven to be causative in a few women in POF cohorts by direct sequencing; 6, strong candidate, supported by mutation screening studies in POF cohorts, weak or no functional studies; 5, strong candidate, supported by genome-wide association studies (GWAS); 4, proven to cause syndrome-related candidate with or without screening in sporadic POF; 3, weak candidate and/or contradictory mutation screening studies, weak cohort and/or case; 2, weak candidate, incidental finding and/or supported by only animal studies and/or negative mutation screening studies; 1, insufficient association or studies (GWAS included).
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Genetics of premature ovarian failure Bilgin and Kovanci &
Recently, Murray et al. [18 ], in a large study, reported that FMR1 premutation in women with POF was not as prevalent as previous estimates suggested. They found the prevalence of the premutation was only 2% in POF, 0.7% in early menopause (menopause between the ages of 40 and 45 years) and 0.4% in controls. Guo et al. [19] confirmed that the premutation was also uncommon in Chinese women with POF. In this study, abnormally low number of CGG repeats was also associated with an adverse effect on ovarian function. Accumulation of mutated FMR1 mRNA leading to accelerated follicular atresia is long believed to be the pathogenesis [20]. Elizur et al. [21] recently studied the role of mRNA accumulation in granulosa cells. They reported an association between ovarian function and CGG repeats, and proposed mRNA-mediated toxicity in granulosa cells might be the reason for ovarian failure.
GENES INVOLVED IN REPRODUCTIVE PHYSIOLOGY The evidence for the potential linkage between POF and genetic variations of female reproductive hormones and their receptors is inconsistent. The mutation screening studies reporting linkage with POF are as follows.
two protein damaging variants 1303 C/T and 1310 G/A in the aromatase gene. The same variant was also reported in another female pseudohermaphrodism case with hypergonadotropic hypogonadism [31]. Recently, a potentially damaging novel variant (p.Ala306_Ser314dup) was identified in a 32-year old Indian woman with streak ovaries [32].
17,20-lyase Lee et al. [33] identified a compound heterozygous mutation (p.His373Leu/p.Glu383fs) of 17,20-lyase gene in a Korean woman with POF. However, p.His373Leu change has been known to be common in East Asia. Belgini et al. [34] also reported p.W406R and p.R362C variants in familial Brazilian POF cases.
Inhibin family No variants in INHB have been reported. However, several studies reported a link between variants in the INHA gene and POF. A variant (p.Ala57Thr) was weakly associated with POF in New Zealander, Italian and Indian cohorts [35–37]. Although a meta-analysis made an effort to conclude that this change may serve as a susceptibility factor for POF [38], we believe this association is weak as functional studies are lacking.
Progesterone receptor membrane component 1
Follicle stimulating hormone receptor
Mansouri et al. [22] reported a deleterious variant (p.H165R) in a mixed POF cohort of Swedish and Italian descent. However, in a recent study, Wang et al. [23] failed to detect the same variant in a Chinese cohort with POF. Nevertheless, this gene remains to be a good candidate based on the evidence from the functional studies [24].
A study conducted in a Finnish population reported a variant (c.C566T) in the FSHR gene [39] and suggested a link with POF. However, later studies consistently failed to detect causative variants in Argentinian, Brazilian, North American and New Zealander populations [40–43]. FSHR variants seem to be limited to one ethnic group.
Estrogen receptor a
GENES DEDUCED FROM ANIMAL MODELS AND OOCYTE SPECIFICITY
Single nucleotide polymorphisms (SNPs) such as 397 T/C and 351 A/G in estrogen receptor a have been reported to be a risk factor for POF although initial studies reported controversial results [25–27]. Recently, restriction enzyme PvuII polymorphism was associated with POF in a Brazilian cohort [28]. Both PvuII and XbaI polymorphisms were replicated in a Chinese cohort [29]. Sequencing and functional studies are needed to confirm the association between these polymorphisms and POF.
Multiple candidate genes have been identified based on animal models [e.g., NOBOX, GDF9, BMP15, factor in the germline alpha (FIGLA), spermatogenesis and oogenesis specific basic helix-loop-helix 2 (SOHLH2) and steroidogenic factor 1 (SF-1)] and most of them still lack human studies (see supplementary table for details, http://links.lww.com/ COOG/A25).
Newborn ovary homeobox Aromatase Ito et al. [30] reported an 18-year old with primary amenorrhea and normal karyotype. The patient had
The phenotype of female mice lacking Nobox gene resembles human POF [44]. Qin et al. [45] reported a causative (p.Arg355His) variant in a Caucasian
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cohort with POF; however, they failed to detect any causative variants in a Chinese population. In a mixed cohort of POF (Caucasian and African), Bouilly et al. [46] identified novel variants (p.R303X, p.G91W, p.R117W, p.S342T and p.V350L) and suggested haploinsufficiency as a molecular mechanism for POF. They reported that NOBOX loss-offunction variants accounted for 6.2% of the cases in their cohort. NOBOX remains to be a very strong candidate gene.
Growth differentiation factor 9 and bone morphogenetic protein 15 These genes form heterodimers and function together in follicular development. Animal studies suggested a critical function of GDF9 on regulation of granulosa cell proliferation either alone or in coordination with BMP15 [47]. However, the results of mutation analyses with human individuals are contradictory especially for BMP15 gene. A recent GWAS reported that two homozygous BMP15 variants in female sheep, FecX(Gr)/FecX(Gr) and FecX(O)/ FecX(O), resulted in hyperprolificacy [48]. Norling et al. [49] found that CNVs in the promoter region of the GDF9 gene were associated with POF. However, this was a descriptive study without functional experiments and replication studies are needed.
Factor in the germline alpha Animal models and expression studies consistently supported the essential role of FIGLA in oocyte growth and regulation of zona pellucida genes [50,51]. Zhao et al. [52] reported that a subset of Chinese women with POF harbor p.140 delN mutation that was proven to be disruptive by functional studies. Recently, another variant (p.Arg83Cys) of FIGLA was associated with POF in an Indian cohort [53]. Lin et al. [54] studied with Figla-Cre transgenic mice and revealed apoptosisrelated perinatal loss of oocytes. Based on all these evidences, FIGLA is a very promising candidate gene, and further human studies are necessary.
Spermatogenesis and oogenesis specific basic helix-loop-helix 2 Mouse models strongly support the SOHLH2 gene’s role on primordial follicle assembly [55,56]. Qin et al. [57] recently published the mutation screening results of a large mixed cohort with POF in which novel variants were identified (p.Glu79Lys, p.Glu105Gly in Chinese and c.530þ6T>G in Serbian women). They suggested that disrupted expression, transactivation or homo/heterodimerization of the 170
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SOHLH2 protein might result in ovarian failure. Further studies are needed to confirm this gene as a strong candidate.
Steroidogenic factor 1 nuclear SF-1 (known as NR5A1) knockout mice show disrupted follicular development as a result of granulosa cell malfunction [58]. Several variants of the SF-1 gene in different ethnic cohorts were reported to be associated with POF by Lakhal et al. [59] and Lourenc¸o et al. [60]. Recently, Harrison et al. [61] reported SF-1 microdeletion in a family with 46,XX POF. However, they failed to replicate their finding in a separate POF cohort of 36 women. Although SF-1 plays a central role in gonadal development and interacts with the genes involved in steroidogenesis and folliculogenesis, it seems to be a weak candidate for POF as functional studies did not consistently identify deleterious variants.
SYNDROMES ASSOCIATED WITH PREMATURE OVARIAN FAILURE Syndromes with POF phenotype and the genes associated with them are as follows, blepharophimosis–ptosis–epicanthus inversus syndrome (FOXL2), Perrault syndrome (HSD17B4, HARS2, LARS2 and CLPP), Marinesco-Sjogren syndrome (SIL1), galactosemia (GALT), ovarian leukodystrophy [EIF2B (EIF2B2, EIF2B4 and EIF2B5)], autoimmune polyendocrine syndrome type 1 (AIRE), carbohydrate-deficient glycoprotein syndrome type 1 (PMM2), Cushing proximal symphalangism (NOG) and Albright’s hereditary osteodystrophy (GNAS). See the supplementary table for the details, http://links.lww.com/COOG/A25.
GENES IDENTIFIED BY GENOME-WIDE ASSOCIATION STUDIES Tagged by the SNPs, GWAS can point out certain regions of the genome that harbor candidate genes. Most of the genes discovered are not uniformly involved in the currently known reproductive pathways. This seems to be promising for identifying new candidate genes using GWAS. ADAMTS19, as a known player in animal folliculogenesis, was also discovered by a GWAS [10, 62–64]. Recently, the susceptibility to POF resulting from epistasis (interaction between nonallelic genes) between polymorphisms of the ADAMTS family (ADAMTS19, ADAMTS16) and other genes (IGF2R, TSHB and ACVR2B) was reported [65–67]. The ADAMTS family deserves more attention based on these findings. PTHB1 was another gene that was Volume 27 Number 3 June 2015
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GENES IDENTIFIED BY CASE REPORTS
identified by a GWAS [68]. In another GWAS, Kang et al. [69] discovered a POF-susceptible haplotype (‘GAAAG’) and a POF-resistant haplotype (‘TGTGC’) of PTHB1. Both GWAS suffered from the same weakness of having small sample sizes. Currently, we have substantial data from multiple large scale GWAS performed in the past few years [62,70,71]. Several susceptibility regions for age at natural menopause, early menopause and POF have been reported. Of these regions, the one that was most consistently identified in different ethnic populations is 19q13.42 [71–74]. In the 19q13.42 region, several genes (TMEM150B, BRSK1, HSPBP1, COX6B2, SUV420H2, IL11, NLRP11, NLRP4, SAPS1, FAM71E2 and RFPL4A) were tagged by an SNP or in high linkage [75] (see Table 2 for other candidate genes identified by large GWAS). A recent Serbian study [77] failed to show any association between POF and the BRSK1 gene mutations in this region although a Chinese study previously reported an association [9]. Our group screened the TMEM150 and BRSK1 genes in a predominantly Caucasian cohort with POF and failed to detect any deleterious variants (in submission). GWAS are conducted with large cohorts and have enough statistical power. However, other methodological issues and small effect size are important weaknesses and point out the need for novel approaches in the search for the genetic perturbation causing POF.
A Korean study reported a POF case with a partial Xp duplication and Xq deletion in spite of an initial normal female karyotype and emphasized the importance of further molecular genetic investigation such as aCGH [78]. A Chinese study underlined the same issue when reporting a POF individual with a supernumerary i(Y)(q10) chromosome [79]. Pierce et al. [80] found mutations in the LARS2 gene (c.1565C>A in a Palestinian family and a compound heterozygous c.1077delT/c.1886C>T in a Slovenian family) that encodes mitochondrial leucyl-tRNA synthetase. They suggested the LARS2 gene might be critical for the maintenance of ovarian function. Similar to LARS2, aberrations of HARS2 and CLPP genes were also reported to be involved in mammalian gonadal dysgenesis (compound heterozygous in HARS2, p.L200V/p.V368L and homozygous mutations in CLPP, c.433A>C, c.440G>C and c.270þ4A>G) [81,82]. A large familial POF study identified a frameshift mutation in the STAG3 gene that encodes a meiosisspecific subunit cohesion component. The study also showed that fetal oocytes were arrested in Stag3 null female mice [83]. Wang et al. [84] recently identified HFM1 gene mutations in two sisters and a Chinese cohort with POF. They suggested biallelic mutations in this gene resulted in a recessive mode of POF.
Table 2. Candidate genes from genome-wide association studies GWAS finding
Ethnic background
Identified genes
Reference
ANM (meta-analysis with 6510 women)
African-American
AMHR2, RHBLD2, PRIM1, HK3/UIMC1, BRSK1/TMEM150B, MCM8
[74]
ANM (meta-analysis with 38 968 women)
European
RHBDL2, EXO1, FNDC4, TLK1, METAP1D, HELQ, RNF44, UIMC1/HK3, SYCP2L, BAT2, ASH2L, FSHB/MPPED2, PRIM1, KPNA3, TDRD3, POLG, GSPT1, BRSK1/TMEM150B, NLRP11, MCM8, CLDN11, SLC44A4, GPR124, DYNC1H1, BANP, F5, CYP1B1, ESR1, AMHR2, HSDB1, APOE, FAM175A, FANCI, DMC1, IL11
[62,71,74,75]
ANM (replication study with 3533 women) POF (Dutch cohort of 60 patients)
Chinese
TMEM150B, NLRP11, BRSK1, RHBDL2, POLG, ASH2L ADAMTS19
[73]
MCM8 BRSK1 TMEM150B MCM8 TMEM150B, ASH2L, HSD17B6, PRIM1, BAT2, NLRP11, RHBDL2, TDRD3, TLK1, SYCP2L, FNDC4, POLG, UIMC1, EXO1, HELQ
[70]
Caucasian
ANM/EM (replication study with 3468 women)
US Hispanic
EM/POF (meta-analysis 3493 women with EM, 1108 women with POF)
European
[10]
[76]
ANM, age at natural menopause; EM, early menopause (defined as menopause before 45 years of age); GWAS, genome-wide association studies; POF, premature ovarian failure.
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Most of these genes that are identified in case reports are yet to be investigated in large cohorts with idiopathic POF.
FUTURE DIRECTIONS AND WORKUP Heritability studies consistently support the genetic roots of POF. Although a large number of candidate genes were proposed, a few of them were studied extensively and supported by strong scientific evidence. Some of the candidate genes identified by animal models also seem to be promising in human studies (e.g., NOBOX, GDF9 and FIGLA), whereas others are yet to be replicated (e.g., WNT4, H1FOO, NANOS3 and SOHLH2). Although the effect size is small, GWAS are still promising resources. In this regard, the 19q13.42 region seems to be a strong candidate. Only a few confirmational studies have been (e.g., BRSK1/ TMEM150B) conducted on the candidate genes in this region. Thus, further studies on these genes and many other ones in the same region are needed in large POF cohorts with different ethnic groups. Novel molecular mechanisms of regulation and modification of gene expression might lead to new perspectives. Studies demonstrated that more than 90% of all SNPs are located in regulatory or intergenic regions [85]. Thus, it would not be surprising to discover an association between POF and various regulatory elements such as microRNAs (miRNA), long intervening noncoding RNAs and piwi-interacting RNAs (piRNAs). miRNAs are small, nonprotein-coding RNAs that may provide new insights into the molecular mechanisms of POF. Accumulating evidence suggests that miRNAs are involved in steroidogenesis, ovulation and follicle development [86 ]. Dai et al. [87] demonstrated the regulatory role of miR-133b on FOXL2-mediated estrogen production in granulosa cells. Sirotkin et al. [88,89] investigated miRNAs in human ovarian cells using a genome-wide screen and suggested a role for miRNAs in proliferation and apoptosis. Yang et al. [90] studied miRNAs in the plasma of women with POF and suggested that mir-23a may have an effect on granulosa cell apoptosis. Recently, Rah et al. [91 ] analyzed certain miRNA polymorphisms in Korean women with POF. Although none of the polymorphisms alone was associated with POF, they suggested that gene–gene interaction between miR-146 and miR-196a2 might lead to POF susceptibility. piRNAs are also thought to help maintain the integrity of mammalian germ line cells. Our group investigated 10 piRNAs in the 19q13.42 region. However, we did not detect any variants (in submission). We believe more studies are necessary focusing on the perturbations of the regulatory or intergenic regions of the genome. &&
&
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In summary, investigating the FMR1 gene status along with karyotype analysis of women with POF is definitely the starting point of the genetic workup for women with POF. High resolution cytogenetic techniques such as aCGH should be considered if the traditional karyotyping is found to be normal. We highly recommend every clinician encourage women with POF to participate in research studies. Acknowledgements None. Financial support and sponsorship This work was supported by the Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA. Conflicts of interest There are no conflicts of interest.
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Genetics of premature ovarian failure Bilgin and Kovanci 18. Murray A, Schoemaker MJ, Bennett CE, et al. Population-based estimates of the prevalence of FMR1 expansion mutations in women with early menopause and primary ovarian insufficiency. Genet Med 2014; 16:19–24. This is a large well designed study investigating the prevalence of FMR1 premutation in women with POF and early menopause compared with a large number of controls. It is a landmark article which will be frequently cited. 19. Guo T, Qin Y, Jiao X, et al. FMR1 premutation is an uncommon explanation for premature ovarian failure in Han Chinese. PLoS One 2014; 9:e103316. 20. Allen EG, Sullivan AK, Marcus M, et al. Examination of reproductive aging milestones among women who carry the FMR1 premutation. Hum Reprod 2007; 22:2142–2152. 21. Elizur SE, Lebovitz O, Derech-Haim S, et al. Elevated levels of FMR1 mRNA in granulosa cells are associated with low ovarian reserve in FMR1 premutation carriers. PLoS One 2014; 9:e105121. 22. Mansouri MR, Schuster J, Badhai J, et al. Alterations in the expression, structure and function of progesterone receptor membrane component-1 (PGRMC1) in premature ovarian failure. Hum Mol Genet 2008; 17:3776– 3783. 23. Wang JL, Li SL, Qin YY, Chen ZJ. Analysis of progesterone receptor membrane component 1 mutation in Han Chinese women with premature ovarian failure. Reprod Biomed Online 2014; 29:640–643. 24. Peluso JJ. Progesterone receptor membrane component 1 and its role in ovarian follicle growth. Front Neurosci 2013; 7:99. 25. Bretherick KL, Hanna CW, Currie LM, et al. Estrogen receptor alpha gene polymorphisms are associated with idiopathic premature ovarian failure. Fertil Steril 2008; 89:318–324. 26. Yoon SH, Choi YM, Hong MA, et al. Estrogen receptor {alpha} gene polymorphisms in patients with idiopathic premature ovarian failure. Hum Reprod 2010; 25:283–287. 27. Syrrou M, Georgiou I, Patsalis PC, et al. Fragile X premutations and (TA)n estrogen receptor polymorphism in women with ovarian dysfunction. Am J Med Genet 1999; 84:306–308. 28. Cordts EB, Santos AA, Peluso C, et al. Risk of premature ovarian failure is associated to the PvuII polymorphism at estrogen receptor gene ESR1. J Assist Reprod Genet 2012; 29:1421–1425. 29. Liu L, Tan R, Cui Y, et al. Estrogen receptor a gene (ESR1) polymorphisms associated with idiopathic premature ovarian failure in Chinese women. Gynecol Endocrinol 2013; 29:182–185. 30. Ito Y, Fisher CR, Conte FA, et al. Molecular basis of aromatase deficiency in an adult female with sexual infantilism and polycystic ovaries. Proc Natl Acad Sci U S A 1993; 90:11673–11677. 31. Conte FA, Grumbach MM, Ito Y, et al. A syndrome of female pseudohermaphrodism, hypergonadotropic hypogonadism, and multicystic ovaries associated with missense mutations in the gene encoding aromatase (P450arom). J Clin Endocrinol Metab 1994; 78:1287–1292. 32. Gagliardi L, Scott HS, Feng J, Torpy DJ. A case of aromatase deficiency due to a novel CYP19A1 mutation. BMC Endocr Disord 2014; 14:16. 33. Lee ES, Kim M, Moon S, et al. A new compound heterozygous mutation in the CYP17A1 gene in a female with 17a-hydroxylase/17,20-lyase deficiency. Gynecol Endocrinol 2013; 29:720–723. 34. Belgini DR, Mello MP, Baptista MT, et al. Six new cases confirm the clinical molecular profile of complete combined 17a-hydroxylase/17,20-lyase deficiency in Brazil. Arq Bras Endocrinol Metabol 2010; 54:711–716. 35. Shelling AN, Burton KA, Chand AL, et al. Inhibin: a candidate gene for premature ovarian failure. Hum Reprod 2000; 15:2644–2649. 36. Marozzi A, Porta C, Vegetti W, et al. Mutation analysis of the inhibin alpha gene in a cohort of Italian women affected by ovarian failure. Hum Reprod 2002; 17:1741–1745. 37. Dixit H, Deendayal M, Singh L. Mutational analysis of the mature peptide region of inhibin genes in Indian women with ovarian failure. Hum Reprod 2004; 19:1760–1764. 38. Chand AL, Harrison CA, Shelling AN. Inhibin and premature ovarian failure. Hum Reprod Update 2010; 16:39–50. 39. Aittoma¨ki K, Lucena JL, Pakarinen P, et al. Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell 1995; 82:959–968. 40. Sundblad V, Chiauzzi VA, Escobar ME, et al. Screening of FSH receptor gene in Argentine women with premature ovarian failure (POF). Mol Cell Endocrinol 2004; 222:53–59. 41. Vilodre LC, Kohek MB, Spritzer PM. Screening of follicle-stimulating hormone receptor gene in women with premature ovarian failure in southern Brazil and associations. J Endocrinol Invest 2008; 31:552–557. 42. Layman LC, Amde S, Cohen DP, et al. The Finnish follicle-stimulating hormone receptor gene mutation is rare in North American women with 46,XX ovarian failure. Fertil Steril 1998; 69:300–302. 43. Woad KJ, Prendergast D, Winship IM, Shelling AN. FSH receptor gene variants are rarely associated with premature ovarian failure. Reprod Biomed Online 2013; 26:396–399. 44. Lechowska A, Bilinski S, Choi Y, et al. Premature ovarian failure in noboxdeficient mice is caused by defects in somatic cell invasion and germ cell cyst breakdown. J Assist Reprod Genet 2011; 28:583–589. 45. Qin Y, Shi Y, Zhao Y, et al. Mutation analysis of NOBOX homeodomain in Chinese women with premature ovarian failure. Fertil Steril 2009; 91 (4 Suppl):1507–1509.
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46. Bouilly J, Bachelot A, Broutin I, et al. Novel NOBOX loss-of-function mutations account for 6.2% of cases in a large primary ovarian insufficiency cohort. Hum Mutat 2011; 32:1108–1113. 47. Carabatsos MJ, Elvin J, Matzuk MM, Albertini DF. Characterization of oocyte and follicle development in growth differentiation factor-9-deficient mice. Dev Biol 1998; 204:373–384. 48. Demars J, Fabre S, Sarry J, et al. Genome-wide association studies identify two novel BMP15 mutations responsible for an atypical hyperprolificacy phenotype in sheep. PLoS Genet 2013; 9:e1003482. 49. Norling A, Hirschberg AL, Rodriguez-Wallberg KA, et al. Identification of a duplication within the GDF9 gene and novel candidate genes for primary ovarian insufficiency (POI) by a customized high-resolution array comparative genomic hybridization platform. Hum Reprod 2014; 29:1818– 1827. 50. Rajkovic A, Matzuk MM. Functional analysis of oocyte-expressed genes using transgenic models. Mol Cell Endocrinol 2002; 187:5–9. 51. Bayne RA, Martins da Silva SJ, Anderson RA. Increased expression of the FIGLA transcription factor is associated with primordial follicle formation in the human fetal ovary. Mol Hum Reprod 2004; 10:373–381. 52. Zhao H, Chen ZJ, Qin Y, et al. Transcription factor FIGLA is mutated in patients with premature ovarian failure. Am J Hum Genet 2008; 82:1342– 1348. 53. Tosh D, Rani HS, Murty US, et al. Mutational analysis of the FIGLA gene in women with idiopathic premature ovarian failure. Menopause 2015. [Epub ahead of print] 54. Lin RS, Jimenez-Movilla M, Dean J. Figla-Cre transgenic mice expressing myristoylated EGFP in germ cells provide a model for investigating perinatal oocyte dynamics. PLoS One 2014; 9:e84477. 55. Chen CL, Fu XF, Wang LQ, et al. Primordial follicle assembly was regulated by Notch signaling pathway in the mice. Mol Biol Rep 2014; 41:1891– 1899. 56. Toyoda S, Yoshimura T, Mizuta J, Miyazaki J. Auto-regulation of the Sohlh1 gene by the SOHLH2/SOHLH1/SP1 complex: implications for early spermatogenesis and oogenesis. PLoS One 2014; 9:e101681. 57. Qin Y, Jiao X, Dalgleish R, et al. Novel variants in the SOHLH2 gene are implicated in human premature ovarian failure. Fertil Steril 2014; 101:1104.e6– 1109.e6. 58. Jeyasuria P, Ikeda Y, Jamin SP, et al. Cell-specific knockout of steroidogenic factor 1 reveals its essential roles in gonadal function. Mol Endocrinol 2004; 18:1610–1619. 59. Lakhal B, Ben-Hadj-Khalifa S, Bouali N, et al. Mutational screening of SF1 and WNT4 in Tunisian women with premature ovarian failure. Gene 2012; 509: 298–301. 60. Lourenc¸o D, Brauner R, Lin L, et al. Mutations in NR5A1 associated with ovarian insufficiency. N Engl J Med 2009; 360:1200–1210. 61. Harrison SM, Campbell IM, Keays M, et al. Screening and familial characterization of copy-number variations in NR5A1 in 46,XY disorders of sex development and premature ovarian failure. Am J Med Genet A 2013; 161A:2487–2494. 62. Stolk L, Zhai G, van Meurs JB, et al. Loci at chromosomes 13, 19 and 20 influence age at natural menopause. Nat Genet 2009; 41:645–647. 63. Menke DB, Page DC. Sexually dimorphic gene expression in the developing mouse gonad. Gene Expr Patterns 2002; 2:359–367. 64. Richards JS, Hernandez-Gonzalez I, Gonzalez-Robayna I, et al. Regulated expression of ADAMTS family members in follicles and cumulus oocyte complexes: evidence for specific and redundant patterns during ovulation. Biol Reprod 2005; 72:1241–1255. 65. Pyun JA, Kim S, Cha DH, Kwack K. Epistasis between IGF2R and ADAMTS19 polymorphisms associates with premature ovarian failure. Hum Reprod 2013; 28:3146–3154. 66. Pyun JA, Kim S, Cha DH, Kwack K. Epistasis between polymorphisms in TSHB and ADAMTS16 is associated with premature ovarian failure. Menopause 2014; 21:890–895. 67. Pyun JA, Kim S, Kwack K. Epistasis between polymorphisms in ACVR2B and ADAMTS19 is associated with premature ovarian failure. Menopause 2015; 22:212–216. 68. Christin-Maitre S, Tachdjian G. Genome-wide association study and premature ovarian failure. Ann Endocrinol 2010; 71:218–221. 69. Kang H, Lee SK, Kim MH, et al. Parathyroid hormone-responsive B1 gene is associated with premature ovarian failure. Hum Reprod 2008; 23:1457– 1465. 70. Chen CT, Ferna´ndez-Rhodes L, Brzyski RG, et al. Replication of loci influencing ages at menarche and menopause in Hispanic women: the Women’s Health Initiative SHARe Study. Hum Mol Genet 2012; 21: 1419–1432. 71. He C, Kraft P, Chen C, et al. Genome-wide association studies identify loci associated with age at menarche and age at natural menopause. Nat Genet 2009; 41:724–728. 72. He C, Kraft P, Chasman DI, et al. A large-scale candidate gene association study of age at menarche and age at natural menopause. Hum Genet 2010; 128:515–527. 73. Shen C, Delahanty RJ, Gao YT, et al. Evaluating GWAS-identified SNPs for age at natural menopause among chinese women. PLoS One 2013; 8:e58766.
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Fertility, IVF and reproductive genetics 74. Chen CT, Liu CT, Chen GK, et al. Meta-analysis of loci associated with age at natural menopause in African-American women. Hum Mol Genet 2014; 23:3327–3342. 75. Stolk L, Perry JR, Chasman DI, et al. Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways. Nat Genet 2012; 44:260–268. 76. Perry JR, Corre T, Esko T, Chasman DI. A genome-wide association study of early menopause and the combined impact of identified variants. Hum Mol Genet 2013; 22:1465–1472. 77. Qin Y, Vujovic S, Li G, et al. Ethnic specificity of variants of the ESR1, HK3, BRSK1 genes and the 8q22.3 locus: no association with premature ovarian failure (POF) in Serbian women. Maturitas 2014; 77:64–67. 78. Kim MK, Seok HH, Kim YS, et al. Molecular genetic and cytogenetic characterization of a partial Xp duplication and Xq deletion in a patient with premature ovarian failure. Gene 2014; 534:54–59. 79. Zeng H, Kong H, Xiao Y, et al. Investigation of a rare supernumerary i(Y)(q10) chromosome in a patient with premature ovarian failure. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2014; 31:192–195. 80. Pierce SB, Gersak K, Michaelson-Cohen R, et al. Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to premature ovarian failure and hearing loss in Perrault syndrome. Am J Hum Genet 2013; 92:614–620. 81. Pierce SB, Chisholm KM, Lynch ED, et al. Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome. Proc Natl Acad Sci U S A 2011; 108:6543– 6548. 82. Jenkinson EM, Rehman AU, Walsh T, et al. Perrault syndrome is caused by recessive mutations in CLPP, encoding a mitochondrial ATP-dependent chambered protease. Am J Hum Genet 2013; 92:605–613.
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83. Caburet S, Arboleda VA, Llano E, et al. Mutant cohesin in premature ovarian failure. N Engl J Med 2014; 370:943–949. 84. Wang J, Zhang W, Jiang H, Wu BL; Primary Ovarian Insufficiency Collaboration. Mutations in HFM1 in recessive primary ovarian insufficiency. N Engl J Med 2014; 370:972–974. 85. Kumar V, Westra HJ, Karjalainen J, et al. Human disease-associated genetic variation impacts large intergenic noncoding RNA expression. PLoS Genet 2013; 9:e1003201. 86. Imbar T, Eisenberg I. Regulatory role of microRNAs in ovarian function. Fertil && Steril 2014; 101:1524–1530. This is an outstanding article every Ob–Gyn who is interested in learning about miRNAs should read. 87. Dai A, Sun H, Fang T, et al. MicroRNA-133b stimulates ovarian estradiol synthesis by targeting Foxl2. FEBS Lett 2013; 587:2474–2482. 88. Sirotkin AV, Laukova´ M, Ovcharenko D, et al. Identification of microRNAs controlling human ovarian cell proliferation and apoptosis. J Cell Physiol 2010; 223:49–56. 89. Sirotkin AV, Ovcharenko D, Grossmann R, et al. Identification of microRNAs controlling human ovarian cell steroidogenesis via a genome-scale screen. J Cell Physiol 2009; 219:415–420. 90. Yang X, Zhou Y, Peng S, et al. Differentially expressed plasma microRNAs in premature ovarian failure patients and the potential regulatory function of mir23a in granulosa cell apoptosis. Reproduction 2012; 144:235–244. 91. Rah H, Jeon YJ, Shim SH, et al. Association of miR-146aC>G, miR& 196a2T>C, and miR-499A>G polymorphisms with risk of premature ovarian failure in Korean women. Reprod Sci 2013; 20:60–68. This is the first article investigating the association between POF and noncoding regions of our genome. It is a call for more studies looking at the noncoding regions of the genome and their associations with genetic diseases.
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Genetics of premature ovarian failure Ekrem M. Bilgin and Ertug Kovanci
Purpose of review To provide an overview on the genetic basis of premature ovarian failure (POF) with specific attention to recently published molecular genetic studies. Recent findings POF is an insidious cause of female infertility. Despite enormous efforts to understand the genetic pathogenesis, we know almost nothing but Turner syndrome and Fragile X syndrome. The era of genomewide association studies opened a new window into the understanding of the complex, polygenic nature of ovarian failure by identifying several candidate regions. Most of the genes in these regions are waiting for confirmation in isolated POF cohorts. Recently, molecular evidence on the regulatory role of small noncoding RNAs in folliculogenesis and oocyte development began to emerge. The association between certain microRNA polymorphisms and POF has been reported. Summary Although there exist numerous candidate genes in the literature, a few of them have comprehensive and consistent molecular workup that showed strong genotype/phenotype association. Keywords candidate genes, genetics, infertility, mutations, premature ovarian failure
INTRODUCTION Premature ovarian failure (POF) is a significant cause for female infertility. Natural cessation of menses is 51 years on average [1]. POF is defined as a cessation of menses before age of 40. The diagnosis is made based on increased gonadotropin levels (follicle stimulation hormone >20 IU/l). Leading clinical features are amenorrhea with hypoestrogenism [2] and its prevalence is one to three in 100 women by age 40 [3,4]. It is preceded by a gradual decline in ovarian function. Although there are some well known causes [X chromosome perturbations, Fragile X mental retardation 1 (FMR1) permutation], the majority of the POF cases are idiopathic. It appears that there is a strong genetic basis [5,6] for age at menopause as it is similar among first-degree relatives such as sister– sister and mother–daughter pairs [7]. POF is a complex condition which most likely has a polygenic nature. Defects in multiple genes cause ovarian failure in animal models. Both autosomal and sex chromosome perturbations are associated with POF in women. It is reasonable to begin with searching candidate genes in genetic pathways related to germ cell development. Many oocytespecific genes have been defined [e.g., growth differentiation factor 9 (GDF9), bone morphogenetic protein 15 (BMP15) and newborn ovary homeobox
(NOBOX)] by the help of animal studies and each plays a crucial role at key points during oocyte development. Studies on rare syndromes associated with POF (e.g., blepharophimosis, ptosis and epicanthus inversus syndrome and Perrault syndrome) have been helping us identify new candidate genes as well [8]. The genetic variations of basic reproductive hormones and their receptors [e.g., estrogen receptor, follicle stimulating hormone receptor (FSHR)] have always been promising, although the results are far from being explanatory in most cases. Recently, genome-wide association studies (GWAS) have provided us with several novel candidate regions and many more candidate genes [9,10]. In this article, we summarize the recently published data on candidate genes, genetic variants and made an effort to highlight a new perspective on genetics of POF. We also developed a grading system for all candidate genes (Table 1). Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA Correspondence to Ertug Kovanci, MD, Obstetrics and Gynecology, Baylor College of Medicine, 7900 Fannin Street, Suite 4400, Houston, TX 77054, USA. Tel: +1 713 512 7064; fax: +1 713 512 7829; e-mail: [email protected] Curr Opin Obstet Gynecol 2015, 27:167–174 DOI:10.1097/GCO.0000000000000177
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KEY POINTS GWAS are a valuable resource for identification of new candidate genes for POF. Regulatory role of small noncoding RNAs in folliculogenesis and oocyte development is becoming apparent. Novel approaches in the search of genetic mechanisms of POF are needed.
CHROMOSOMAL ABNORMALITIES This group is a well known cause of POF. Particularly, X chromosome abnormalities are estimated to constitute up to 13% of cases [11]. Main aberrations include monosomies, trisomies, translocations, deletions and copy number variants (CNVs) [2]. The numerous POF case reports have led to the identification of ‘critical regions’ on both the short and long arms of the X chromosome such as Xq13.3Xq27 and Xp13.1-p11. Autosomal chromosomal abnormalities and balanced translocations can also be associated with POF.
Turner syndrome Turner syndrome is observed with an incidence of one in 2500 female births that makes it the most common X chromosome abnormality leading to POF. Cytogenetically, mosaicism is frequent. The specific molecular pathways affecting ovarian
function in Turner syndrome patients are yet to be discovered. Germ cell atresia and the extent of ovarian failure vary based on the mosaicism level. In a recent study on X chromosome mosaicism, Castronovo et al. [12] concluded that 10% euploid cell line might lead to spontaneous menarche. Their cohort consisted of 40 women with Turner syndrome (six women with spontaneous menarche and 34 women with primary amenorrhea). By using array comparative genomic hybridization (aCGH) analysis and quantitative PCR confirmation, they identified CNVs that involved autosomal and X-linked ovary-related loci containing novel candidate genes (pregnancy-associated plasma protein A and phosphodiesterase 8A). They suggested gene dosage as a significant mechanism in ovarian phenotype of women with Turner syndrome.
Fragile X syndrome The gene associated with Fragile X syndrome is located on chromosome Xq27.3. This gene called FMR1 results in Fragile X syndrome if its trinucleotide (CGG) repeats are expanded over 200 (full mutation). On the contrary, premutation (55–199 CGG repeats) is associated with POF and subsequent infertility. However, women with the full mutation are not at risk for POF. In Caucasian women, 20–28% of carriers develop POF [13,14]. On the contrary, carrier status in women with POF was found to be ranging from 0.8 to 14% depending on the family history [15–17].
Table 1. Grading system for candidate genes Grade
Gene name
8
To be found
7
NOBOX
6
CDKN1B, CITED2, CPEB1, CSPG5, CXCL12, HFM1, MSH5, NANOS3, TGFBR3, FIGLA, GDF9
5
ALOX12, BRSK1, LAMC1, MCM8/MCM9, NLRP11, SYCP2L, TMEM150B
4
AIRE, ATM, BMPR1B, CLPP, FMR1/FMR2, FOXL2, GALT, GNAS, HARS2, HSD17B4, LARS2, NOG, PMM2, POU5F1, SHOX
3
ADAMTS19, ADAMTS16, AMHR2, BMP15, CYP17A1, DIAPH2, DMC1, DNAH6, EIF2B2/EIF2B4/EIF2B5, ESR1, FOXO1, FOXO3, GREM1, HK3, INHA/INHB, KDR, LHR, SF-1, MT-ATP6, POF1B, SALL4, SOHLH2, SMARCC1, SYCE1, TAF4B, TNFSF11, TSPYL6, USP9X, XIST, XPNPEP2, ZP1/ZP2/ZP3, ZFR2
2
ADAMTS1, AR, AKT1, AGTR2, ALOX15, BAX, BCL2, BDNF, CENPI, CX37/CX43, DACH2, DAZL, DMRT1, DLX5/DLX6, ESR2, FOXO4, FST, BRCA1/BRCA2, GPR3, H1FOO, KISS1, KIT, LATS1, LEP, LHX8, MATER, MTHFR, NGF, NXF5, PDK1, PIN1, POLG, PGRMC1, PTHB1, PTEN, RPS6, SKP2, SPO11, TSC1, YY1, VEGF, WNT4, WT1
1
CBX3, HS6ST1/HS6ST2, KISS1R, PDE3A, RFPL4, SMAD1/SMAD5, RHBDL2, PRIM1, UIMC1, EXO1, FNDC4, TLK1, METAP1D, HELQ, RNF44, BAT2, ASH2L, MPPED2, KPNA3, TDRD3, GSPT1, CLDN11, SLC44A4, GPR124, DYNC1H1, BANP, F5, CYP1B1, HSDB1, APOE, FAM175A, FANCI, IL11, HSD17B6
8, Strong candidate, supported by animal studies and/or functional studies and proven to be causative in majority of women in premature ovarian failure (POF) cohorts by direct sequencing; 7, strong candidate, supported by animal studies and/or functional studies and proven to be causative in a few women in POF cohorts by direct sequencing; 6, strong candidate, supported by mutation screening studies in POF cohorts, weak or no functional studies; 5, strong candidate, supported by genome-wide association studies (GWAS); 4, proven to cause syndrome-related candidate with or without screening in sporadic POF; 3, weak candidate and/or contradictory mutation screening studies, weak cohort and/or case; 2, weak candidate, incidental finding and/or supported by only animal studies and/or negative mutation screening studies; 1, insufficient association or studies (GWAS included).
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Genetics of premature ovarian failure Bilgin and Kovanci &
Recently, Murray et al. [18 ], in a large study, reported that FMR1 premutation in women with POF was not as prevalent as previous estimates suggested. They found the prevalence of the premutation was only 2% in POF, 0.7% in early menopause (menopause between the ages of 40 and 45 years) and 0.4% in controls. Guo et al. [19] confirmed that the premutation was also uncommon in Chinese women with POF. In this study, abnormally low number of CGG repeats was also associated with an adverse effect on ovarian function. Accumulation of mutated FMR1 mRNA leading to accelerated follicular atresia is long believed to be the pathogenesis [20]. Elizur et al. [21] recently studied the role of mRNA accumulation in granulosa cells. They reported an association between ovarian function and CGG repeats, and proposed mRNA-mediated toxicity in granulosa cells might be the reason for ovarian failure.
GENES INVOLVED IN REPRODUCTIVE PHYSIOLOGY The evidence for the potential linkage between POF and genetic variations of female reproductive hormones and their receptors is inconsistent. The mutation screening studies reporting linkage with POF are as follows.
two protein damaging variants 1303 C/T and 1310 G/A in the aromatase gene. The same variant was also reported in another female pseudohermaphrodism case with hypergonadotropic hypogonadism [31]. Recently, a potentially damaging novel variant (p.Ala306_Ser314dup) was identified in a 32-year old Indian woman with streak ovaries [32].
17,20-lyase Lee et al. [33] identified a compound heterozygous mutation (p.His373Leu/p.Glu383fs) of 17,20-lyase gene in a Korean woman with POF. However, p.His373Leu change has been known to be common in East Asia. Belgini et al. [34] also reported p.W406R and p.R362C variants in familial Brazilian POF cases.
Inhibin family No variants in INHB have been reported. However, several studies reported a link between variants in the INHA gene and POF. A variant (p.Ala57Thr) was weakly associated with POF in New Zealander, Italian and Indian cohorts [35–37]. Although a meta-analysis made an effort to conclude that this change may serve as a susceptibility factor for POF [38], we believe this association is weak as functional studies are lacking.
Progesterone receptor membrane component 1
Follicle stimulating hormone receptor
Mansouri et al. [22] reported a deleterious variant (p.H165R) in a mixed POF cohort of Swedish and Italian descent. However, in a recent study, Wang et al. [23] failed to detect the same variant in a Chinese cohort with POF. Nevertheless, this gene remains to be a good candidate based on the evidence from the functional studies [24].
A study conducted in a Finnish population reported a variant (c.C566T) in the FSHR gene [39] and suggested a link with POF. However, later studies consistently failed to detect causative variants in Argentinian, Brazilian, North American and New Zealander populations [40–43]. FSHR variants seem to be limited to one ethnic group.
Estrogen receptor a
GENES DEDUCED FROM ANIMAL MODELS AND OOCYTE SPECIFICITY
Single nucleotide polymorphisms (SNPs) such as 397 T/C and 351 A/G in estrogen receptor a have been reported to be a risk factor for POF although initial studies reported controversial results [25–27]. Recently, restriction enzyme PvuII polymorphism was associated with POF in a Brazilian cohort [28]. Both PvuII and XbaI polymorphisms were replicated in a Chinese cohort [29]. Sequencing and functional studies are needed to confirm the association between these polymorphisms and POF.
Multiple candidate genes have been identified based on animal models [e.g., NOBOX, GDF9, BMP15, factor in the germline alpha (FIGLA), spermatogenesis and oogenesis specific basic helix-loop-helix 2 (SOHLH2) and steroidogenic factor 1 (SF-1)] and most of them still lack human studies (see supplementary table for details, http://links.lww.com/ COOG/A25).
Newborn ovary homeobox Aromatase Ito et al. [30] reported an 18-year old with primary amenorrhea and normal karyotype. The patient had
The phenotype of female mice lacking Nobox gene resembles human POF [44]. Qin et al. [45] reported a causative (p.Arg355His) variant in a Caucasian
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cohort with POF; however, they failed to detect any causative variants in a Chinese population. In a mixed cohort of POF (Caucasian and African), Bouilly et al. [46] identified novel variants (p.R303X, p.G91W, p.R117W, p.S342T and p.V350L) and suggested haploinsufficiency as a molecular mechanism for POF. They reported that NOBOX loss-offunction variants accounted for 6.2% of the cases in their cohort. NOBOX remains to be a very strong candidate gene.
Growth differentiation factor 9 and bone morphogenetic protein 15 These genes form heterodimers and function together in follicular development. Animal studies suggested a critical function of GDF9 on regulation of granulosa cell proliferation either alone or in coordination with BMP15 [47]. However, the results of mutation analyses with human individuals are contradictory especially for BMP15 gene. A recent GWAS reported that two homozygous BMP15 variants in female sheep, FecX(Gr)/FecX(Gr) and FecX(O)/ FecX(O), resulted in hyperprolificacy [48]. Norling et al. [49] found that CNVs in the promoter region of the GDF9 gene were associated with POF. However, this was a descriptive study without functional experiments and replication studies are needed.
Factor in the germline alpha Animal models and expression studies consistently supported the essential role of FIGLA in oocyte growth and regulation of zona pellucida genes [50,51]. Zhao et al. [52] reported that a subset of Chinese women with POF harbor p.140 delN mutation that was proven to be disruptive by functional studies. Recently, another variant (p.Arg83Cys) of FIGLA was associated with POF in an Indian cohort [53]. Lin et al. [54] studied with Figla-Cre transgenic mice and revealed apoptosisrelated perinatal loss of oocytes. Based on all these evidences, FIGLA is a very promising candidate gene, and further human studies are necessary.
Spermatogenesis and oogenesis specific basic helix-loop-helix 2 Mouse models strongly support the SOHLH2 gene’s role on primordial follicle assembly [55,56]. Qin et al. [57] recently published the mutation screening results of a large mixed cohort with POF in which novel variants were identified (p.Glu79Lys, p.Glu105Gly in Chinese and c.530þ6T>G in Serbian women). They suggested that disrupted expression, transactivation or homo/heterodimerization of the 170
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SOHLH2 protein might result in ovarian failure. Further studies are needed to confirm this gene as a strong candidate.
Steroidogenic factor 1 nuclear SF-1 (known as NR5A1) knockout mice show disrupted follicular development as a result of granulosa cell malfunction [58]. Several variants of the SF-1 gene in different ethnic cohorts were reported to be associated with POF by Lakhal et al. [59] and Lourenc¸o et al. [60]. Recently, Harrison et al. [61] reported SF-1 microdeletion in a family with 46,XX POF. However, they failed to replicate their finding in a separate POF cohort of 36 women. Although SF-1 plays a central role in gonadal development and interacts with the genes involved in steroidogenesis and folliculogenesis, it seems to be a weak candidate for POF as functional studies did not consistently identify deleterious variants.
SYNDROMES ASSOCIATED WITH PREMATURE OVARIAN FAILURE Syndromes with POF phenotype and the genes associated with them are as follows, blepharophimosis–ptosis–epicanthus inversus syndrome (FOXL2), Perrault syndrome (HSD17B4, HARS2, LARS2 and CLPP), Marinesco-Sjogren syndrome (SIL1), galactosemia (GALT), ovarian leukodystrophy [EIF2B (EIF2B2, EIF2B4 and EIF2B5)], autoimmune polyendocrine syndrome type 1 (AIRE), carbohydrate-deficient glycoprotein syndrome type 1 (PMM2), Cushing proximal symphalangism (NOG) and Albright’s hereditary osteodystrophy (GNAS). See the supplementary table for the details, http://links.lww.com/COOG/A25.
GENES IDENTIFIED BY GENOME-WIDE ASSOCIATION STUDIES Tagged by the SNPs, GWAS can point out certain regions of the genome that harbor candidate genes. Most of the genes discovered are not uniformly involved in the currently known reproductive pathways. This seems to be promising for identifying new candidate genes using GWAS. ADAMTS19, as a known player in animal folliculogenesis, was also discovered by a GWAS [10, 62–64]. Recently, the susceptibility to POF resulting from epistasis (interaction between nonallelic genes) between polymorphisms of the ADAMTS family (ADAMTS19, ADAMTS16) and other genes (IGF2R, TSHB and ACVR2B) was reported [65–67]. The ADAMTS family deserves more attention based on these findings. PTHB1 was another gene that was Volume 27 Number 3 June 2015
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Genetics of premature ovarian failure Bilgin and Kovanci
GENES IDENTIFIED BY CASE REPORTS
identified by a GWAS [68]. In another GWAS, Kang et al. [69] discovered a POF-susceptible haplotype (‘GAAAG’) and a POF-resistant haplotype (‘TGTGC’) of PTHB1. Both GWAS suffered from the same weakness of having small sample sizes. Currently, we have substantial data from multiple large scale GWAS performed in the past few years [62,70,71]. Several susceptibility regions for age at natural menopause, early menopause and POF have been reported. Of these regions, the one that was most consistently identified in different ethnic populations is 19q13.42 [71–74]. In the 19q13.42 region, several genes (TMEM150B, BRSK1, HSPBP1, COX6B2, SUV420H2, IL11, NLRP11, NLRP4, SAPS1, FAM71E2 and RFPL4A) were tagged by an SNP or in high linkage [75] (see Table 2 for other candidate genes identified by large GWAS). A recent Serbian study [77] failed to show any association between POF and the BRSK1 gene mutations in this region although a Chinese study previously reported an association [9]. Our group screened the TMEM150 and BRSK1 genes in a predominantly Caucasian cohort with POF and failed to detect any deleterious variants (in submission). GWAS are conducted with large cohorts and have enough statistical power. However, other methodological issues and small effect size are important weaknesses and point out the need for novel approaches in the search for the genetic perturbation causing POF.
A Korean study reported a POF case with a partial Xp duplication and Xq deletion in spite of an initial normal female karyotype and emphasized the importance of further molecular genetic investigation such as aCGH [78]. A Chinese study underlined the same issue when reporting a POF individual with a supernumerary i(Y)(q10) chromosome [79]. Pierce et al. [80] found mutations in the LARS2 gene (c.1565C>A in a Palestinian family and a compound heterozygous c.1077delT/c.1886C>T in a Slovenian family) that encodes mitochondrial leucyl-tRNA synthetase. They suggested the LARS2 gene might be critical for the maintenance of ovarian function. Similar to LARS2, aberrations of HARS2 and CLPP genes were also reported to be involved in mammalian gonadal dysgenesis (compound heterozygous in HARS2, p.L200V/p.V368L and homozygous mutations in CLPP, c.433A>C, c.440G>C and c.270þ4A>G) [81,82]. A large familial POF study identified a frameshift mutation in the STAG3 gene that encodes a meiosisspecific subunit cohesion component. The study also showed that fetal oocytes were arrested in Stag3 null female mice [83]. Wang et al. [84] recently identified HFM1 gene mutations in two sisters and a Chinese cohort with POF. They suggested biallelic mutations in this gene resulted in a recessive mode of POF.
Table 2. Candidate genes from genome-wide association studies GWAS finding
Ethnic background
Identified genes
Reference
ANM (meta-analysis with 6510 women)
African-American
AMHR2, RHBLD2, PRIM1, HK3/UIMC1, BRSK1/TMEM150B, MCM8
[74]
ANM (meta-analysis with 38 968 women)
European
RHBDL2, EXO1, FNDC4, TLK1, METAP1D, HELQ, RNF44, UIMC1/HK3, SYCP2L, BAT2, ASH2L, FSHB/MPPED2, PRIM1, KPNA3, TDRD3, POLG, GSPT1, BRSK1/TMEM150B, NLRP11, MCM8, CLDN11, SLC44A4, GPR124, DYNC1H1, BANP, F5, CYP1B1, ESR1, AMHR2, HSDB1, APOE, FAM175A, FANCI, DMC1, IL11
[62,71,74,75]
ANM (replication study with 3533 women) POF (Dutch cohort of 60 patients)
Chinese
TMEM150B, NLRP11, BRSK1, RHBDL2, POLG, ASH2L ADAMTS19
[73]
MCM8 BRSK1 TMEM150B MCM8 TMEM150B, ASH2L, HSD17B6, PRIM1, BAT2, NLRP11, RHBDL2, TDRD3, TLK1, SYCP2L, FNDC4, POLG, UIMC1, EXO1, HELQ
[70]
Caucasian
ANM/EM (replication study with 3468 women)
US Hispanic
EM/POF (meta-analysis 3493 women with EM, 1108 women with POF)
European
[10]
[76]
ANM, age at natural menopause; EM, early menopause (defined as menopause before 45 years of age); GWAS, genome-wide association studies; POF, premature ovarian failure.
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Most of these genes that are identified in case reports are yet to be investigated in large cohorts with idiopathic POF.
FUTURE DIRECTIONS AND WORKUP Heritability studies consistently support the genetic roots of POF. Although a large number of candidate genes were proposed, a few of them were studied extensively and supported by strong scientific evidence. Some of the candidate genes identified by animal models also seem to be promising in human studies (e.g., NOBOX, GDF9 and FIGLA), whereas others are yet to be replicated (e.g., WNT4, H1FOO, NANOS3 and SOHLH2). Although the effect size is small, GWAS are still promising resources. In this regard, the 19q13.42 region seems to be a strong candidate. Only a few confirmational studies have been (e.g., BRSK1/ TMEM150B) conducted on the candidate genes in this region. Thus, further studies on these genes and many other ones in the same region are needed in large POF cohorts with different ethnic groups. Novel molecular mechanisms of regulation and modification of gene expression might lead to new perspectives. Studies demonstrated that more than 90% of all SNPs are located in regulatory or intergenic regions [85]. Thus, it would not be surprising to discover an association between POF and various regulatory elements such as microRNAs (miRNA), long intervening noncoding RNAs and piwi-interacting RNAs (piRNAs). miRNAs are small, nonprotein-coding RNAs that may provide new insights into the molecular mechanisms of POF. Accumulating evidence suggests that miRNAs are involved in steroidogenesis, ovulation and follicle development [86 ]. Dai et al. [87] demonstrated the regulatory role of miR-133b on FOXL2-mediated estrogen production in granulosa cells. Sirotkin et al. [88,89] investigated miRNAs in human ovarian cells using a genome-wide screen and suggested a role for miRNAs in proliferation and apoptosis. Yang et al. [90] studied miRNAs in the plasma of women with POF and suggested that mir-23a may have an effect on granulosa cell apoptosis. Recently, Rah et al. [91 ] analyzed certain miRNA polymorphisms in Korean women with POF. Although none of the polymorphisms alone was associated with POF, they suggested that gene–gene interaction between miR-146 and miR-196a2 might lead to POF susceptibility. piRNAs are also thought to help maintain the integrity of mammalian germ line cells. Our group investigated 10 piRNAs in the 19q13.42 region. However, we did not detect any variants (in submission). We believe more studies are necessary focusing on the perturbations of the regulatory or intergenic regions of the genome. &&
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In summary, investigating the FMR1 gene status along with karyotype analysis of women with POF is definitely the starting point of the genetic workup for women with POF. High resolution cytogenetic techniques such as aCGH should be considered if the traditional karyotyping is found to be normal. We highly recommend every clinician encourage women with POF to participate in research studies. Acknowledgements None. Financial support and sponsorship This work was supported by the Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA. Conflicts of interest There are no conflicts of interest.
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83. Caburet S, Arboleda VA, Llano E, et al. Mutant cohesin in premature ovarian failure. N Engl J Med 2014; 370:943–949. 84. Wang J, Zhang W, Jiang H, Wu BL; Primary Ovarian Insufficiency Collaboration. Mutations in HFM1 in recessive primary ovarian insufficiency. N Engl J Med 2014; 370:972–974. 85. Kumar V, Westra HJ, Karjalainen J, et al. Human disease-associated genetic variation impacts large intergenic noncoding RNA expression. PLoS Genet 2013; 9:e1003201. 86. Imbar T, Eisenberg I. Regulatory role of microRNAs in ovarian function. Fertil && Steril 2014; 101:1524–1530. This is an outstanding article every Ob–Gyn who is interested in learning about miRNAs should read. 87. Dai A, Sun H, Fang T, et al. MicroRNA-133b stimulates ovarian estradiol synthesis by targeting Foxl2. FEBS Lett 2013; 587:2474–2482. 88. Sirotkin AV, Laukova´ M, Ovcharenko D, et al. Identification of microRNAs controlling human ovarian cell proliferation and apoptosis. J Cell Physiol 2010; 223:49–56. 89. Sirotkin AV, Ovcharenko D, Grossmann R, et al. Identification of microRNAs controlling human ovarian cell steroidogenesis via a genome-scale screen. J Cell Physiol 2009; 219:415–420. 90. Yang X, Zhou Y, Peng S, et al. Differentially expressed plasma microRNAs in premature ovarian failure patients and the potential regulatory function of mir23a in granulosa cell apoptosis. Reproduction 2012; 144:235–244. 91. Rah H, Jeon YJ, Shim SH, et al. Association of miR-146aC>G, miR& 196a2T>C, and miR-499A>G polymorphisms with risk of premature ovarian failure in Korean women. Reprod Sci 2013; 20:60–68. This is the first article investigating the association between POF and noncoding regions of our genome. It is a call for more studies looking at the noncoding regions of the genome and their associations with genetic diseases.
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