Analysis of NR5A1 in 142 patients with premature ovarian insufficiency, diminished ovarian reserve, or unexplained infertility.

Ovarian deficiency, including diminished ovarian reserve and premature ovarian insufficiency, represents one of the main causes of female infertility. Little is known of the genetic basis of diminished ovarian reserve, while premature ovarian insufficiency often has a genetic basis, with genes affecting various processes. NR5A1 is a key gene required for gonadal function, and variants are associated with a wide phenotypic spectrum of disorders of sexual development, and are found in 0.26-8% of patients with premature ovarian insufficiency. As there is some debate about the extent of involvement of NR5A1 in the pathogenesis of ovarian deficiency, we performed an in-depth analysis of NR5A1 variants detected in a cohort of 142 patients with premature ovarian insufficiency, diminished ovarian reserve, or unexplained infertility associated with normal ovarian function. We identified rare non-synonymous protein-altering variants in 2.8 % of women with ovarian deficiency and no such variants in our small cohort of women with infertility but normal ovarian function. We observed previously reported variants associated with premature ovarian insufficiency in patients with diminished ovarian reserve, highlighting a genetic relationship between these conditions. We confirmed functional impairment resulting from a p.Val15Met variant, detected for the first time in a patient with premature ovarian insufficiency. The remaining variants were associated with preserved transcriptional activity and localization of NR5A1, indicating that rare NR5A1 variants may be incorrectly curated if functional studies are not undertaken, and/or that NR5A1 variants may have only a subtle impact on protein function and/or confer risk of ovarian deficiency via oligogenic inheritance.

Effects of FSHR polymorphisms on premature ovarian insufficiency in human beings: a meta-analysis.

BACKGROUND: Whether follicle-stimulating hormone receptor (FSHR) polymorphisms are implicated in premature ovarian insufficiency (POI) remains controversial. Thus, we performed this study to explore correlation between FSHR polymorphisms and POI in human beings. METHODS: Literature retrieve was conducted in PubMed, Medline, Embase and CNKI. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. RESULTS: Sixteen studies were enrolled for analyses. No significant relationship with POI was found for rs6165 and rs6166 polymorphisms in overall analyses. Further subgroup analyses revealed that rs6166 polymorphism was significantly associated with the risk of POI in Asians with both FEM and REM. Nevertheless, we failed to detect any significant associations with POI for other ethnicities. CONCLUSIONS: Our findings indicated that FSHR rs6166 polymorphism may serve as a potential genetic biomarker of POI in Asians, but not in other ethnicities.

Novel STAG3 mutations in a Caucasian family with primary ovarian insufficiency.

Primary ovarian insufficiency (POI) affects ~ 1-3, 7% of women under forty and is a public health problem. Most causes are unknown, but an increasing number of genetic causes have been identified recently. The identification of such causes is essential for genetic and therapeutic counseling in patients and their families. We performed whole exome sequencing in two Caucasian sisters displaying non syndromic POI and their unaffected mother. We identified two novel pathogenic variants in STAG3 encoding a meiosis-specific subunit of the cohesin ring, which ensures correct sister chromatid cohesion: a c.3052delC truncating mutation in exon 28 yielding p.Arg1018Aspfs*14, and a c.659T > G substitution in exon seven yielding p.Leu220Arg. Leu220, highly conserved throughout species, belongs to the STAG domain conserved with other mitotic subunits of the cohesion complex STAG1 and 2. In silico analysis reveals that this substitution markedly impacts the structure of this domain. The truncation removes the last 206 C-terminal residues, not conserved in STAG1 and 2, supporting an important specific role in STAG3, especially meiosis. This is the first occurrence of STAG3 mutations in a Caucasian family. Very little is known about the function of STAG proteins domains. The "knock out-like" phenotype described here supports the crucial role of a single residue in the STAG domain and of the C-terminal region in STAG3 function. In conclusion, this observation shows the necessity to perform the genetic study of POI worldwide including STAG3. This could lead to appropriate genetic counseling and long term follow-up since these patients may develop ovarian tumors.

Novel FSHR mutations in Han Chinese women with sporadic premature ovarian insufficiency.

Premature ovarian insufficiency (POI) is characterized by amenorrhea and elevated levels of follicle-stimulating hormone (FSH, usually > 25 IU/L) before 40 years of age. To identify the relationship between FSHR mutations and sporadic POI patients of Han Chinese descent, we performed Sanger sequencing of FSHR gene in 192 sporadic POI patients and 192 matched controls of Han Chinese descent. Two heterozygous missense variants, c.793A > G (p.M265V) and c.1789C > A (p.L597I), were identified exclusively in POI patients. Functional studies showed that both mutants were expressed on the cell surface, while p.L597I showed decreased membrane localization compared with wild-type FSHR. Moreover, FSH-induced cAMP production and ERK1/2 phosphorylation were reduced in the cells transfected with p.L597I mutant, but not in the cells transfected with p.M265V mutant. In addition, two single-nucleotide polymorphisms (SNPs), rs1394205 (c.-29G > A) and rs140106399 (c.*111 T > C), were identified in both POI group and control group with significantly different genotypic and allelic distributions. These results indicated that dysfunctional FSHR due to mutation or SNPs might explain a fraction of sporadic POI cases in Han Chinese population.

Association analysis between HFM1 variation and primary ovarian insufficiency in Chinese women.

HFM1 is a meiosis-specific gene and expressed in germ-line tissues. More recently, evidence has indicated that variations in HFM1 gene could be causative for primary ovarian insufficiency (POI), also known as premature ovarian failure. The aim of this study was to investigate the association between HFM1 gene variants and sporadic POI in Chinese women. A total of 138 POI patients and 316 healthy controls (matched for ethnic background, sex, and age of the patients) were recruited in this study. We screened the entire HFM1 coding region by direct sequencing in all subjects and identified six variants of HFM1 gene in POI group, namely c.148G>A/p.Glu50Lys, c.1241A>C/p.His414Pro, c.2325C>A/p.Phe775Leu, c.3367T>C/p.Ser1123Pro, c.3580C>T/p.Arg1194Cys, and c.1686-1G>C. The variation rate of HFM1 in POI group is significantly higher than control group (p < 0.01). The p.His414Pro and p.Arg1194Cys were predicted to be probably damaging to the HFM1 protein function, while p.Glu50Lys, p.Phe775Leu and p.Ser1123Pro mutants might not have any deleterious effect on the structure or function of the protein by online predictors. Taken together, our data suggested that HFM1 gene might be associated with primary ovarian insufficiency in Chinese population.

Single nucleotide polymorphisms in premature ovarian failure-associated genes in a Chinese Hui population.

Premature ovarian failure (POF) is an ovarian defect characterized by the premature depletion of ovarian follicles in individuals <40 years old, and is a major cause of infertility in females. Genetic factors are considered to be responsible for the development of POF, however, the exact pathogenesis remains to be elucidated in the majority of cases. In the present study, the single nucleotide polymorphisms (SNPs) of growth differentiation factor 9 (GDF9), bone morphogenetic protein 15 (BMP15), inhibin ßB (INHBB) and follicle stimulating hormone receptor (FSHR) genes were investigated, and their association with POF in a Chinese Hui population of the Ningxia Hui Autonomous Region in western China was evaluated. Peripheral blood samples were collected from 63 patients diagnosed with POF (POF group) and 58 normal control individuals (control group), from which the genomic DNA was isolated. The GDF9, BMP15, INHBB and FSHR genes were amplified using polymerase chain reaction assays, and their SNPs were determined by sequencing. In the four SNPs identified across the GDF9 loci, D57Y (169G>T), rs1049127 (546G>A), rs254286 (447C>T) and rs254285 (969C>G), the frequencies of the 546G>A genotype and allele A were significantly higher in the POF group, compared with the normal control group (34.92, vs. 6.90%; P<0.05 and 19.05, vs. 3.23%; P<0.05, respectively), while no significant differences were observed in the occurrence of the c.447C>T and c.969C>G mutations between the two groups (60.32, vs. 50% and 50.79, vs. 55.17%, respectively). The c.169G>T mutation within the GDF9 gene was only detected in two patients with POF, and the mutation did not occur in the normal control group. A total of three SNPs were detected within the BMP15 gene, including rs3810682 (-9C>G), rs79377927 (788_789insTCT) and rs17003221 (852C>T), and no significant differences were observed in the frequencies of the -9C>G and 852C>T genotypes between the POF and control groups (7.94, vs. 6.90% and 4.76, vs. 3.45%, respectively). The 788_789insTCT genotype was detected in only two patients with POF. A novel mutation, c.1095C>A, was identified in exon 2 of the INHBB gene, however, no significant difference was found in the occurrence of the mutation between the two groups (30.16, vs. 22.41%; P>0.05). The rs6165 (919G>A) and rs6166 (2039G>A) SNPs were detected in exon 10 of the FSHR gene; however, no significant difference was observed in the genotype frequencies between the two groups (92.06, vs. 91.38% and 96.83, vs. 93.10%, respectively). These results demonstrated that GDF9 c.169G>T (D57Y), c.546G>A (rs1049127), and BMP15 rs79377927 (788_789insTCT) were associated with POF in the Chinese Hui population.

MicroRNA-22-3p is down-regulated in the plasma of Han Chinese patients with premature ovarian failure.

OBJECTIVE: To determine whether plasma microRNAs (miRNAs) are differentially expressed between women with and without premature ovarian failure (POF), and to uncover the association of miRNAs with risk of POF. DESIGN: Microarray with real-time polymerase chain reaction validation. SETTING: University hospital. PATIENT(S): A total of 140 individuals with premature ovarian failure (POF) and 140 age- and body mass index-matched control subjects of Han Chinese ancestry. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Relative miRNA expression levels in plasma of POF and control group. RESULT(S): Fifty-one differentially expressed miRNAs were identified by chip-based discovery stage between ten patients with POF and ten control subjects, among which nine miRNAs (let-7b-5p, let-7c, miR-15b-5p, miR-22-3p, miR-23a-3p, miR-23b-3p, miR-24-3p, miR-151a-5p, and miR-151b) were selected and validated. The relative expression level of miR-22-3p was significantly down-regulated in POF compared with control subjects. MiR-22-3p yielded a receiver operating characteristic (ROC) curve area of 0.668 (95% confidence interval 0.602-0.733) in discriminating POF from controls. In addition, logistic binary regression analysis and linear regression analysis showed the miR-22-3p to be a protective factor for POF (odds ratio 0.766, 95% CI 0.643-0.912) and negatively associated with serum FSH. Furthermore, bioinformatics analysis indicated that the target function of miR-22-3p was involved in apoptosis, endocytosis, and tumorigenesis. CONCLUSION(S): Mir-22-3p showed a lower expression level in POF and was modestly effective in distinguishing POF from control subjects. The decreased expression of miR-22-3p in plasma of POF may reflect the diminished ovarian reserve and be a consequence of the pathologic process of POF.

Transcription factor SOHLH1 potentially associated with primary ovarian insufficiency.

OBJECTIVE: To investigate whether gene variants of SOHLH1 exist in Chinese and Serbian patients with primary ovarian insufficiency (POI). DESIGN: Case-control genetic study. SETTING: University hospitals. PATIENT(S): A total of 364 Han Chinese and 197 Serbian women with nonsyndromic POI and ethnically matched controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): SOHLH1 gene sequencing. RESULT(S): We found 10 novel heterozygous variants in our cohorts of 561 women with POI but none in the 600 ethnically matched controls. Statistical and bioinformatic analyses indicated that three of the eight variants in Chinese POI cases are potentially disease causing. They comprise two missense variants (p.Ser317Phe and p.Glu376Lys) that might each change activity of the SOHLH1 protein as a transcription factor and one variant (c.*118C>T) located in the 3' untranslated region of the SOHLH1 gene, which might generate a new binding site for the microRNA hsa-miR-888-5p. Of the two variants in the Serbian POI cases, both were synonymous, and no missense variant was identified. The allele frequencies of some known single-nucleotide polymorphisms were statistically significantly different between patients and controls in both the Chinese and Serbian groups. CONCLUSION(S): Our results suggest that SOHLH1 may be regarded as a new candidate gene for POI.

Analysis of progesterone receptor membrane component 1 mutation in Han Chinese women with premature ovarian failure.

The gene PGRMC1 is highly expressed in the granulose and luteal cells of rodent and primate ovaries. Its role in anti-apoptosis and regulating cell-cycle progression suggests a role in regulating follicle growth. The hypothesis is supported by the study in mice and studies in Sweden. In this study, the coding exons of PGRMC1 were sequenced among 196 Chinese women with premature ovarian failure (POF) and 200 controls, and one novel missense mutation was identified (C.556C>T, p. Pro186Ser) in the POF group and one novel SNP (C.533C>T, p. Trh177Ile) was identified in both groups. The mutation is not considered causative because protein prediction did not indicate a deleterious effect. It is concluded that coding mutations of PGRMC1 do not seem to be a common cause of the disease in Han Chinese women. Future studies in larger cohorts from other ethnic groups are necessary to establish the role of PGRMC1 in POF.

An interpretive description of chemotherapy-induced premature menopause among Latinas with breast cancer.

PURPOSE/OBJECTIVES: To describe the experience of chemotherapy-induced premature menopause (CIPM) among Latinas, explore how CIPM was assimilated into the breast cancer experience, and relate measured acculturation levels to the CIPM experience. RESEARCH APPROACH: Interpretive descriptive method from a feminist inquiry lens. SETTING: Telephone interviews with participants from 12 states in the United States. PARTICIPANTS: 20 Latinas who experienced CIPM after treatment for breast cancer. METHODOLOGIC APPROACH: In-depth interviews and the Brief Acculturation Scale for Hispanics were used to elicit data, with interpreter assistance as needed. FINDINGS: One overarching theme, Bigger Than Menopause, and three subthemes, Experiencing Menopause, Ever-Changing Landscape, and Working Through the Experience, were found. PARTICIPANTS' ability to assimilate CIPM into the breast cancer experience was affected by the magnitude of physiologic and psychosocial effects, access to health care, information and support, sense of control, and acculturation level. CONCLUSIONS: The CIPM experience for Latinas with breast cancer is multifaceted, with less acculturated Latinas facing multiple barriers in accessing health care, treatment, information, and support. INTERPRETATION: PARTICIPANTS described CIPM as part of a larger context that included physiologic and psychosocial effects and affected participants' ability to assimilate CIPM into the breast cancer experience. The impact of low acculturation and barriers experienced were elucidated as factors associated with assimilating CIPM into the breast cancer experience.

Impact of premature ovarian failure on mortality and morbidity among Chinese women.

OBJECTIVE: To evaluate associations of premature ovarian failure (POF) with mortality and morbidity in Asian populations. METHODS: We identified 1,003 cases of POF among 36,402 postmenopausal women who participated in the Shanghai Women's Health Study, a population-based cohort study. Cox regression and logistic regression models were applied in data analysis. RESULTS: After adjustment for potential confounding factors, we found that POF increased the risk of total and cancer-specific mortality (HR (95%CIs): 1.29 (1.08-1.54) and 1.38 (1.05-1.81), respectively). POF was also associated with high prevalence of autoimmune disease (OR (95%CI): 1.56 (1.04-2.35)) but decreased incidence of breast cancer (OR (95%CI): 0.59 (0.38-0.91)). Similar results were observed when hormone replacement therapy users were excluded from the analysis. POF is associated with high waist-to-hip ratio. CONCLUSIONS: Our results suggest that women with POF experience increased mortality and that these women may benefit from heightened surveillance and appropriate interventions.

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.

OBJECTIVE: To identify whether variants found in a large Han Chinese cohort - 8q22.3 SNPs rs3847153 and rs3108910; and one SNP each in HK3 (rs2278493), ESR1 (rs2234693) and BRSK1 (rs12611091) - are associated with premature ovarian failure (POF) in a different ethnic group (Serbian). DESIGN: Case-control genetic association study in 197 Serbian POF cases and 552 matched controls. RESULTS: None of the SNPs found associated with POF in Chinese cohort were found to be associated in the Serbian sample. CONCLUSIONS: In contrast to Han Chinese, no association was found between POF in Serbian women and any of the four tested loci: 8q22.3, HK3, ESR1 and BRSK1. This indicates that ethnically distinct populations may show differences in gene-regulating pathways and genes causing POF.

FMR1 CGG allele length in Israeli BRCA1/BRCA2 mutation carriers and the general population display distinct distribution patterns.

Premature ovarian failure and diminished ovarian reserve have been noted both in female BRCA1/BRCA2 mutation carriers and in carriers of the Fragile X syndrome FMR1 gene CGG repeat size premutation. Based on the observation that BRCA mutation carriers do not harbour long CGG repeats in the FMR1 gene, it was hypothesized that BRCA-associated premature ovarian failure is mediated via FMR1. To test this notion, we evaluated the distribution of constitutional FMR1 genotypes in 188 BRCA1/BRCA2 mutation-positive Jewish Ashkenazi women and 15 708 female, mostly Ashkenazi controls in Israel. BRCA1/BRCA2 mutation carriers displayed a unique distribution of FMR1 genotypes compared with controls (p = 0·018) with a prominence of the shorter CGG alleles (<26 repeats). There was no allele size distribution differences within BRCA carriers when comparing cancer free (n = 95) and breast cancer affected women (n = 93) (p = 0·43). In conclusion, BRCA mutation carriers exhibit a distinct CGG FMR1 repeat size pattern compared with the general population, but it is unlikely to account for the reported diminished ovarian reserve or act as a modifier breast cancer gene in BRCA mutation carriers.

Tumor necrosis factor-alpha promoter polymorphisms are associated with idiopathic primary ovarian insufficiency in Korean women.

OBJECTIVE: To investigate the possible association between primary ovarian insufficiency (POI) and TNF-α gene polymorphisms in Korean women. DESIGN: Case-control study. SETTING: An urban university-based hospital in South Korea. PATIENT(S): A cohort of 135 Korean POI patients and 236 controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): We analyzed TNF-α gene variants of all participants using the polymerase chain reaction-restriction fragment length polymorphism assay. RESULT(S): The TNF-α -1031TC+CC, -238GA+AA, -1031TC+CC/-308GG, -1031TT/-308GA+AA, -1031TC+CC/-238GA+AA, and -308GG/-238GA+AA genotypes were significantly more frequent in POI patients than in controls. Among the haplotypes for the three TNF-α loci, the -1031C/-308G/-238A haplotype was more frequent in POI patients than in controls and conferred POI susceptibility. In analyses of two loci, the -1031T/-308A, -1031C/-308G, -1031C/-238A, and -308G/-238A haplotypes were more frequent in POI patients. CONCLUSION(S): The TNF-α -1031C and -238A alleles had strong association with POI. The TNF-α -308A allele showed limited significance for POI risk with the presence of the -1031T allele. Our data suggest that the minor alleles of TNF-α promoter polymorphisms may increase POI risk in Korean women.

Cytogenetic analysis of 531 Chinese women with premature ovarian failure.

BACKGROUND: This retrospective cohort study was to determine the frequency and types of chromosomal abnormalities in Han Chinese women with well-documented premature ovarian failure (POF). METHODS: Karyotype analysis and correlation to phenotypes were performed on 531 Chinese patients with proven POF (FSH > 40 mIU/ml) attending four reproductive centers in China. G-banded metaphase chromosomes were prepared and analyzed, with mosaicism excluded by counting up to 100 cells from lymphocytes. RESULTS: Chromosomal abnormalities were present in 64 of 531 (12.1%) POF cases, of which 32 were X-structural aberrations (7 mosaic): 15 del(Xq), 2 del(Xp), 11 isochromosomes [6 i(Xp); 5 i(Xq)], 1 ring chromosome (mosaic), 1 inversion (mosaic), 1 isodicentric chromosome and 1 complex arrangement. Nine non-mosaic X-autosome translocations were detected, all but 1 involving Xq. Aneuploidy without a structurally abnormal X was found in 19 cases: 7 non-mosaic 45,X, 9 45,X mosaicisms and 3 47,XXX (1 mosaic with 46,XX line). Karyotypic abnormalities were more frequent in patients with primary amenorrhea (15/70, 21.4%) than those with secondary amenorrhea (49/461, 10.6%; P = 0.01). 45,X and 45,X/46,XX mosaicism were the complements most frequently associated with primary amenorrhea (46.7%). Two of the three cases with 46,XY or 45,X/46,XY karyotype presented with 'secondary amenorrhea'. One balanced autosomal Robertsonian translocation was also detected. CONCLUSIONS: The overall prevalence of chromosomal abnormalities was 12.1% in this first large scale report of chromosomal aberrations in Chinese women with POF. In one of the largest samples of women with POF reported from any population, the prevalence of X-structural abnormalities, X-autosome translocations and X aneuploidy confirms the essential role X chromosomal abnormalities play in POF.

Haplotype and mutation analysis of the TGFBR3 gene in Chinese women with idiopathic premature ovarian failure.

This study screened the TGFBR3 mutations in Chinese patients with idiopathic premature ovarian failure (POF) to gain a better understanding the genetic aetiology of POF. One hundred twelve Chinese patients with idiopathic POF and 110 women from normal controls were examined. The coding region and respective flanking intronic regions of the TGFBR3 gene were amplified by the PCR, and the DNA fragments were directly sequenced. Twenty-eight sequence variants, including 12 novel variants, were identified. These novel variants included three missense mutations, two synonymous mutations, and seven mutations in the intronic region. Three novel exonic missense variants were p.E458G, p.P824L, and p.I836V. The c.566-216G>A, c.566-71C>T, c.2022T>C, c.2502A>G, and c.2568G>A variants represented significantly different genotype distribution between POF cases and the controls. The binary logistic regression analysis of c.566-216G>A, c.566-71C>T, and c.2502A>G variants were significantly associated with the POF patients and the ATTAG haplotype was most significantly over-represented as compared with controls (P = 0.00121). The ATTGG and GCTGG haplotypes were significantly higher in controls than in patients (P = 0.00113 and 0.00055, respectively). Other less frequent haplotypes, such as GCCGA, was only present in the patients (P = 0.00066). GTTGG was only present in the controls (P = 0.00001). Significant diversity of genotype distribution and haplotype analysis suggested that TGFBR3 mutations may be responsible for the genetic aetiology of idiopathic POF in Chinese patients.

Genetic variants and environmental factors associated with hormonal markers of ovarian reserve in Caucasian and African American women.

BACKGROUND: The ovarian reserve (number and quality of oocytes) is correlated with reproductive potential as well as somatic health, and is likely to have multiple genetic and environmental determinants. Several reproductive hormones are closely linked with the oocyte pool and thus can serve as surrogate markers of ovarian reserve. However, we know little about the underlying genes or genetic variants. METHODS: We analyzed genetic variants across the genome associated with two hormonal markers of ovarian reserve, FSH and anti-Mullerian hormone, in a reproductively normal population of Caucasian (n = 232) and African American (n = 200) women, aged 25-45 years. We also examined the effects of environmental or lifestyle factors on ovarian reserve phenotypes. RESULTS: We identified one variant approaching genome-wide significance (rs6543833; P= 8.07 × 10⁻8) and several nominal variants nearby and within the myeloid-associated differentiation marker-like (MYADML) gene, that were associated with FSH levels in African American women; these were validated in Caucasian women. We also discovered effects of smoking and oral contraceptive use on ovarian reserve phenotypes, with alterations in several reproductive hormones. CONCLUSIONS: This work is the largest study on ovarian reserve in women of reproductive age and is the only genome-wide study on ovarian reserve markers. The genes containing or near the identified variants have no known roles in ovarian biology and represent interesting candidate genes for future investigations. The discovery of genetic markers may lead to better long-range predictions of declining ovarian function, with implications for reproductive and somatic health.

Number of CGG repeats in the FMR1 gene of Japanese patients with primary ovarian insufficiency.

OBJECTIVE: To define the number of CGG repeats in the FMR1 gene of Japanese patients with primary ovarian insufficiency (POI) and normal controls. DESIGN: Retrospective, controlled cohort study. SETTING: Outpatient department of an academic tertiary center. PATIENT(S): One hundred twenty-eight consecutive Japanese patients with sporadic, nonsyndromic POI and 98 controls with normal menstruation. INTERVENTION(S): Deoxyribonucleic acid was obtained from the plasma of each subject. MAIN OUTCOME MEASURE(S): Differences in the distribution of CGG repeat numbers between patients with POI and controls. RESULT(S): Six alleles in the intermediate range and two in the premutation range were found in five and two patients with POI, respectively, but none were identified in normal controls. The prevalence of FMR1 premutation among Japanese POI patients was 1.56% (2 of 128). The prevalence of having >36 CGG repeats in the FMR1 gene was significantly higher in patients with POI than in controls, and age at the onset of amenorrhea was significantly lower in patients with >38 repeats. CONCLUSION(S): More than 36 CGG repeats in the FMR1 might intensify the etiology of POI, at least up to the premutation range.

Mutation analysis of the WNT4 gene in Han Chinese women with premature ovarian failure.

BACKGROUND: The WNT4 gene plays an important role in female sex determination and differentiation. It also contributes to maintaining of the ovaries and the survival of follicles. METHODS: We sequenced the coding region and splice sites of WNT4 in 145 Han Chinese women with premature ovarian failure (POF) and 200 healthy controls. RESULTS: Only one novel variation, in Exon 2 (195C > T), was detected among the women with POF. However, this synonymous variation did not result in a change in amino acid sequence (65 Asp > Asp). No further variants were found in any of the samples. CONCLUSION: Although we cannot provide any evidence that it is a possible disease-causing gene, this study is the first attempt to investigate the possible role of WNT4 in Han Chinese women with POF.

GPR3 may not be a potential candidate gene for premature ovarian failure.

The G protein-coupled receptor gene GPR3 is expressed predominantly in oocytes, and functions in the early development of oocytes in the ovarian follicle. GPR3 is essential for meiotic arrest maintenance in mice, which makes it a candidate gene for premature ovarian failure (POF). The coding region of GPR3 was screened in 100 Chinese POF patients for variants of the GPR3 gene. Except for one novel variant in the 3'UTR region in three subjects and another novel synonymous c.135G-->A variant in one subject, no perturbations were found in the coding region. The results of this study suggested that mutations in GPR3 are not a common cause of POF in Chinese women.