Species: human
Mutation name: None
type: naturally occurring
fertility: fertile
Comment: Imbeaud S, et al 1995 have cloned and mapped the human AMH receptor gene and provide genetic proof that it is required for AMH signalling, by identifying a mutation in the AMH receptor in a patient with persistent Mullerian duct syndrome. The mutation destroys the invariant dinucleotide at the 5' end of the second intron, generating two abnormal mRNAs, one missing the second exon, required for ligand binding, and the other incorporating the first 12 bases of the second intron. The similar phenotypes observed in AMH-deficient and AMH receptor-deficient individuals indicate that the AMH signalling machinery is remarkably simple, consisting of one ligand and one type II receptor.

Species: human
Mutation name: None
type: naturally occurring
fertility: fertile
Comment: Association study of anti-Mullerian hormone and anti-Mullerian hormone type II receptor polymorphisms with idiopathic primary ovarian insufficiency. Yoon SH 2013 et al. STUDY QUESTION Are the genetic polymorphisms of the anti-M?an hormone (AMH) and anti-M?an hormone type II receptor (AMHR2) genes associated with idiopathic primary ovarian insufficiency (POI) in a Korean population? SUMMARY ANSWER The distribution of the AMH and the AMHR2 polymorphisms in a Korean POI population was not significantly different from controls. WHAT IS KNOWN ALREADY AMH plays an important role in regulating both the primordial follicle recruitment and the cyclic selection of the antral follicles. The AMHR2 -482A>G polymorphism was associated with an earlier menopause and nulliparous women with the GG genotype had a 2.6 years earlier onset of menopause compared with the AA genotype women. Therefore, genetic variants in the AMH signal transduction pathway might affect the ovarian function of women. STUDY DESIGN, SIZE, DURATION Case-control study. The subjects consisted of 211 idiopathic POI patients and 233 post-menopausal controls. PARTICIPANTS/MATERIALS, SETTING, METHODS The frequency of the AMH Ile(49)Ser and AMHR2 -482A>G polymorphisms was analyzed in 211 patients with idiopathic POI and in 233 post-menopausal controls, and we also analyzed clinical characteristics, such as age at the time of POI and LH, FSH?as well as estradiol levels according to the specific genotype. Genotyping for the AMH Ile(49)Ser and the AMHR2 -482A>G polymorphisms was performed by a minor groove binder primer/probe Taqman assay. MAIN RESULTS AND THE ROLE OF CHANCE The genotype distributions and allele frequencies for the AMH Ile(49)Ser and the AMHR2 -482A>G polymorphisms were similar between the POI patients and the controls. Within POI population, the AMH Ile(49)Ser and the AMHR2 -482A>G polymorphisms were not associated with age at the time of POI and LH, FSH as well as estradiol levels. Haplotype analysis also showed no significant difference between groups. LIMITATIONS, REASONS FOR CAUTION Study is limited to a Korean population. WIDER IMPLICATIONS OF THE FINDINGS Our findings suggest that genetic variants in the AMH signal transduction pathway may not influence the susceptibility of idiopathic POI. This is the first report on the association between the AMH and AMHR2 polymorphisms and idiopathic POI. STUDY FUNDING/COMPETING INTEREST(S) No conflict of interest exists. This study was supported by a grant of Seoul National University Hospital Research Fund (04-2011-0870). TRIAL REGISTRATION NUMBER: N/A. ///////////////////////// A polymorphism in the AMH type II receptor gene is associated with age at menopause in interaction with parity. Kevenaar ME et al. BACKGROUND Anti-M?an hormone (AMH) inhibits primordial follicle recruitment in the mouse ovary. We hypothesize that in women AMH signaling also regulates the usage of the primordial follicle pool and hence influences the onset of menopause. Since age at menopause has a strong genetic component, we investigated the role of AMH signaling using a candidate gene approach. METHODS In two large population-based cohorts of Dutch post-menopausal women (n = 2381 and n = 248), we examined the association between two polymorphisms, one in the AMH gene and one in the AMH type II receptor (AMHR2) gene, and natural age at menopause. RESULTS The AMH Ile(49)Ser polymorphism (rs10407022) was not associated with age at menopause in either cohort. In the Rotterdam cohort, the AMHR2 -482 A>G polymorphism (rs2002555) was associated with age at menopause in interaction with the number of offspring (P = 0.001). Nulliparous women homozygous for the G-allele entered menopause 2.6 years earlier compared with nulliparous women homozygous for the A-allele (P = 0.005). In the LASA cohort, women with the G/G genotype tended to enter menopause 2.8 years earlier compared with the A/A genotype (P = 0.063). CONCLUSIONS The observed association of the AMHR2 -482 A>G polymorphism with natural age at menopause suggests a role for AMH signaling in the usage of the primordial follicle pool in women.

Species: mouse
Mutation name: None
type: null mutation
fertility: fertile
Comment: Genetic analysis of the M?an-inhibiting substance signal transduction pathway in mammalian sexual differentiation. Mishina Y et al. M?an-inhibiting substance (MIS) is a member of the transforming growth factor-beta (TGF-beta) gene family. MIS expression in males causes the regression of the M?an ducts, an essential process in male sexual differentiation. Recently, an MIS type II receptor gene has been isolated that is expressed during embryogenesis in mesenchymal cells adjacent to the M?an duct epithelium and in Sertoli and granulosa cells of the fetal and adult, male and female gonads, respectively. MIS receptor mutant males develop as internal pseudohermaphrodites, possessing a complete male reproductive tract and also a uterus and oviducts, a phenocopy of MIS ligand-deficient male mice. They express both MIS mRNA and protein, showing that ligand was present, but target organs were hormone-insensitive. All produce sperm, but the majority were infertile because the presence of their female reproductive organs blocks sperm transfer into females. Focal seminiferous tubule atrophy accompanied by Leydig cell hyperplasia was observed and began as early as 2 months of age. The phenotype of MIS ligand/MIS receptor double mutant males was indistinguishable from those of each single mutant. MIS receptor/alpha-inhibin double mutant males developed testicular stromal tumors and large fluid-filled uteri that were identical in phenotype to MIS ligand/alpha-inhibin double mutant males. These studies provide in vivo evidence that MIS is the only ligand of the MIS type II receptor, in contrast to the complexity of other TGF-beta gene family signaling pathways.

Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Increased frequency of the Anti-Mullerian-inhibiting hormone receptor 2 (AMHR2) 482 A>G polymorphism in women with Polycystic Ovary Syndrome (PCOS): Relationship to Luteinizing Hormone (LH) Levels. Georgopoulos NA 2013 et al. Context:The polycystic ovary syndrome (PCOS) is a common and complex disease without a clear pattern of inheritance. AMH has an inhibitory effect on FSH-stimulated follicle growth. Serum AMH levels are higher in women with PCOS than in normovulatory women. The elevated AMH levels may reflect abnormalities at the AMH signaling.Objective:To evaluate the AMHR2 -482 A>G polymorphism's (rs2002555) association with the pathophysiology of PCOS.Design:The AMHR2 -482 A>G polymorphism genotyping were performed in a large cohort of PCOS women as well as in a healthy control group.Setting/Subjects:A total of 858 Caucasian women with PCOS and 309 healthy controls.Intervention(s):Genotyping and hormonal measurement.Main Outcome Measure(s).Hormonal determination was performed in PCOS women.Results:The AMHR2 polymorphism was more common in women with PCOS than in controls (p=0.026). Homozygous AMHR2 -482 A>G gene polymorphisms (GG) were associated with decreased levels of LH (p=0.003) and LH:FSH ratio (p=0.01) in women with PCOS, as well as with lower prolactin levels (p=0.004). No other associations related to AMHR2 -482 A>G polymorphisms were observed in women with PCOS or controls.Conclusion:In this study, the role of the AMHR2 -482 A>G gene polymorphism in the pathogenesis of PCOS has been suggested by the association of the variant with PCOS risk. Thus, further research is needed in order to elucidate a possible association of the AMHR2 -482 A>G gene polymorphism with AMH signaling and impaired ovarian function and its clinical significance in women with PCOS. /////////////////////////

Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Analyzing the possible involvement of anti-Mllerian hormone and anti-Mllerian hormone receptor II single nucleotide polymorphism in infertility. Yoshida Y 2013 et al. PURPOSE We performed TaqMan genotyping assays of anti-Mullerian hormone (AMH) and anti-Mullerian hormone receptor type II (AMHRII) single nucleotide polymorphisms (SNPs) in order to investigate how their frequency and distribution affect infertility treatment outcome. METHODS Eighty Japanese women (advanced age: n?=?51, endometriosis: n?=?18, male infertility as a control: n?=?11) who undertook ART were included in the study, and all couples underwent a full infertility investigation protocol. In order to investigate the natural distribution of SNPs, a naturally pregnant group of 28 subjects was recruited from among women who conceived naturally and subsequently delivered in our department. Genomic DNA was extracted from peripheral blood and genotyping was conducted by TaqMan genotyping assay. The relationship of AMH and AMHRII SNPs and treatment outcome in infertile women. Comparison of allele and genotype frequencies of infertile patients with naturally pregnant women. RESULTS AMHRII -482 A>G homozygote mutation was complicated with ISV 5-6 C>T homozygote mutation and showed a significantly lower oocyte retrieval rate compared with a wild type. Two of 3 cases of AMHRII -482 A>G homozygote mutation were poor responders, and the distribution and frequency of each allele of naturally pregnant women showed no statistical difference compared with infertile women. CONCLUSIONS This study revealed the possible involvement of AMHRII -482 A>G polymorphism on the malfunction of follicular development in Japanese women. /////////////////////////

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: A dominant negative mutation at the ATP binding domain of AMHR2 is associated with a defective anti-Müllerian hormone signaling pathway. Li L et al. (2016) Does a heterozygous mutation in AMHR2, identified in whole-exome sequencings (WES) of patients with primary ovarian insufficiency (POI), cause a defect in anti-Müllerian hormone (AMH) signaling. The I209N mutation at the adenosine triphosphate binding domain of AMHR2 exerts dominant negative defects in the AMH signaling pathway. Previous studies have demonstrated the associations of several sequence variants in AMH or AMHR2 with POI, but no functional assay has been performed to verify whether there was any defect on AMH signaling. Ninety-six unrelated female Chinese Han patients were diagnosed with idiopathic POI and subjected to WES. In silico analysis was done for the sequence variants followed by molecular assays to examine the functional effects of the sequence variants in human granulosa cells. In silico analysis, immunostaining, Western analysis, genome-wide expression analysis, quantitatively polymerase chain reaction were applied to the characterization of the sequence variants. We identified one novel heterozygous missense variant, p.Ala17Glu (A17E), in AMHR2. Subsequently, A17E and two independently reported missense variants, p.Ile209Asn (I209N) and p.Leu354Phe (L354F), were evaluated for effects on the AMH signaling pathway. In silico analysis predicted that all three variants may be deleterious. However, only one variant, I209N, showed severe defects in transducing the AMH signal as well as impaired SMAD1/5/8 phosphorylation. Furthermore, using genome-wide gene expression analysis, we identified genes whose expression was affected by the mutation, these included genes previously reported to participate in AMH signaling as well as newly identified genes. They are EMILIN2, FAM155A, GATA2, HES5, ID1, ID2, RLTPR, SMAD7, CBL, MALAT1 and SMARCA2. Although the in vitro assays demonstrated the causative effect of I209N on AMH signaling, further studies need to validate its long-term effects on folliculogenesis and POI. These results will aid both researchers and clinicians in understanding the molecular pathology of AMH signaling and POI to develop diagnostic assays or therapeutics approaches. .//////////////////

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Functional Genetic Variation in the Anti-Müllerian Hormone Pathway in Women with Polycystic Ovary Syndrome. Gorsic LK et al. (2019) PCOS is a highly heritable, common endocrine disorder characterized by hyperandrogenism, irregular menses and polycystic ovaries. PCOS is often accompanied by elevated levels of anti-Müllerian hormone (AMH). AMH inhibits follicle maturation. AMH also inhibits steroidogenesis through transcriptional repression of CYP17A1. We recently identified 16 rare PCOS-specific pathogenic variants in AMH. To test whether additional members of the AMH signaling pathway also contribute to the etiology of PCOS. Targeted re-sequencing of coding and regulatory regions of AMH and its specific type 2 receptor, AMHR2 was performed on 608 PCOS-affected women and 142 reproductively normal control women. Prediction tools of deleteriousness and in silico evidence of epigenetic modification were used to prioritize variants for functional evaluation. Dual luciferase reporter assays and splicing assays were used to measure the impact of genetic variants on function. We identified 20 additional variants in/near AMH and AMHR2 with significantly reduced signaling activity in in vitro assays. Collectively, from our previous study and reported herein, we have identified a total of 37 variants with impaired activity in/near AMH and AMHR2 in 41 women affected with PCOS, or 6.7% of our PCOS cohort. Furthermore, no functional variants were observed in the 142 phenotyped controls. The functional variants were significantly associated with PCOS in our cohort of 608 women with PCOS and 142 controls (p=2.3 x 10-5) and very strongly associated with PCOS relative to a larger non-Finnish European (gnomAD) population-based control cohort (p<1x10-9). AMH signaling cascade plays an important role in PCOS etiology.//////////////////

Species: human
Mutation name:
type: None
fertility: None
Comment: https://www.ncbi.nlm.nih.gov/pubmed/30786001 Context: Polycystic ovary syndrome (PCOS) is a highly heritable, common endocrine disorder characterized by hyperandrogenism, irregular menses, and polycystic ovaries. PCOS is often accompanied by elevated levels of anti-Müllerian hormone (AMH). AMH inhibits follicle maturation. AMH also inhibits steroidogenesis through transcriptional repression of CYP17A1. We recently identified 16 rare PCOS-specific pathogenic variants in AMH. OBJECTIVE: To test whether additional members of the AMH signaling pathway also contribute to the etiology of PCOS. PARTICIPANTS/DESIGN: Targeted resequencing of coding and regulatory regions of AMH and its specific type 2 receptor, AMHR2, was performed on 608 women affected with PCOS and 142 reproductively normal control women. Prediction tools of deleteriousness and in silico evidence of epigenetic modification were used to prioritize variants for functional evaluation. Dual-luciferase reporter assays and splicing assays were used to measure the impact of genetic variants on function. RESULTS: We identified 20 additional variants in/near AMH and AMHR2 with significantly reduced signaling activity in in vitro assays. Collectively, from our previous study and as reported herein, we have identified a total of 37 variants with impaired activity in/near AMH and AMHR2 in 41 women affected with PCOS, or 6.7% of our PCOS cohort. Furthermore, no functional variants were observed in the 142 phenotyped controls. The functional variants were significantly associated with PCOS in our cohort of 608 women with PCOS and 142 controls (P = 2.3 × 10-5) and very strongly associated with PCOS relative to a larger non-Finnish European (gnomAD) population-based control cohort (P < 1 × 10-9). CONCLUSION: The AMH signaling cascade plays an important role in PCOS etiology

Species: human
Mutation name:
type: None
fertility: None
Comment: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543512/ polycystic ovary syndrome (PCOS) is a highly heritable, common endocrine disorder characterized by hyperandrogenism, irregular menses, and polycystic ovaries. PCOS is often accompanied by elevated levels of anti-Müllerian hormone (AMH). AMH inhibits follicle maturation. AMH also inhibits steroidogenesis through transcriptional repression of CYP17A1. We recently identified 16 rare PCOS-specific pathogenic variants in AMH. Objective: To test whether additional members of the AMH signaling pathway also contribute to the etiology of PCOS. Participants/Design:Targeted resequencing of coding and regulatory regions of AMH and its specific type 2 receptor, AMHR2, was performed on 608 women affected with PCOS and 142 reproductively normal control women. Prediction tools of deleteriousness and in silico evidence of epigenetic modification were used to prioritize variants for functional evaluation. Dual-luciferase reporter assays and splicing assays were used to measure the impact of genetic variants on function. Results: We identified 20 additional variants in/near AMH and AMHR2 with significantly reduced signaling activity in in vitro assays. Collectively, from our previous study and as reported herein, we have identified a total of 37 variants with impaired activity in/near AMH and AMHR2 in 41 women affected with PCOS, or 6.7% of our PCOS cohort. Furthermore, no functional variants were observed in the 142 phenotyped controls. The functional variants were significantly associated with PCOS in our cohort of 608 women with PCOS and 142 controls (P = 2.3 × 10−5) and very strongly associated with PCOS relative to a larger non-Finnish European (gnomAD) population-based control cohort (P < 1 × 10−9).Conclusion: The AMH signaling cascade plays an important role in PCOS etiology.(Gorsic et al. 2019)

Species: human
Mutation name:
type: None
fertility: None
Comment: (Grosic et al 2017) Polycystic ovary syndrome (PCOS), a common endocrine condition, is the leading cause of anovulatory infertility. Objective: Given that common disease-susceptibility variants account for only a small percentage of the estimated PCOS heritability, we tested the hypothesis that rare variants contribute to this deficit in heritability. Design, Setting, and Participants: Unbiased whole-genome sequencing (WGS) of 80 patients with PCOS and 24 reproductively normal control subjects identified potentially deleterious variants in AMH, the gene encoding anti-Müllerian hormone (AMH). Targeted sequencing of AMH of 643 patients with PCOS and 153 control patients was used to replicate WGS findings. Main Outcome Measures: Dual luciferase reporter assays measured the impact of the variants on downstream AMH signaling. Results: We found 24 rare (minor allele frequency < 0.01) AMH variants in patients with PCOS and control subjects; 18 variants were specific to women with PCOS. Seventeen of 18 (94%) PCOS-specific variants had significantly reduced AMH signaling, whereas none of 6 variants observed in control subjects showed significant defects in signaling. Thus, we identified rare AMH coding variants that reduced AMH-mediated signaling in a subset of patients with PCOS. Conclusion: To our knowledge, this study is the first to identify rare genetic variants associated with a common PCOS phenotype. Our findings suggest decreased AMH signaling as a mechanism for the pathogenesis of PCOS. AMH decreases androgen biosynthesis by inhibiting CYP17 activity; a potential mechanism of action for AMH variants in PCOS, therefore, is to increase androgen biosynthesis due to decreased AMH-mediated inhibition of CYP17 activity.

Species: human
Mutation name:
type: None
fertility: None
Comment: Functional Genetic Variation in the Anti-Müllerian Hormone Pathway in Women With Polycystic Ovary Syndrome.(Gorsic LK et al 2019)CONTEXT:Polycystic ovary syndrome (PCOS) is a highly heritable, common endocrine disorder characterized by hyperandrogenism, irregular menses, and polycystic ovaries. PCOS is often accompanied by elevated levels of anti-Müllerian hormone (AMH). AMH inhibits follicle maturation. AMH also inhibits steroidogenesis through transcriptional repression of CYP17A1. We recently identified 16 rare PCOS-specific pathogenic variants in AMH. OBJECTIVE: To test whether additional members of the AMH signaling pathway also contribute to the etiology of PCOS. PARTICIPANTS/DESIGN: Targeted resequencing of coding and regulatory regions of AMH and its specific type 2 receptor, AMHR2, was performed on 608 women affected with PCOS and 142 reproductively normal control women. Prediction tools of deleteriousness and in silico evidence of epigenetic modification were used to prioritize variants for functional evaluation. Dual-luciferase reporter assays and splicing assays were used to measure the impact of genetic variants on function. RESULTS: We identified 20 additional variants in/near AMH and AMHR2 with significantly reduced signaling activity in in vitro assays. Collectively, from our previous study and as reported herein, we have identified a total of 37 variants with impaired activity in/near AMH and AMHR2 in 41 women affected with PCOS, or 6.7% of our PCOS cohort. Furthermore, no functional variants were observed in the 142 phenotyped controls. The functional variants were significantly associated with PCOS in our cohort of 608 women with PCOS and 142 controls (P = 2.3 × 10-5) and very strongly associated with PCOS relative to a larger non-Finnish European (gnomAD) population-based control cohort (P < 1 × 10-9). CONCLUSION: The AMH signaling cascade plays an important role in PCOS etiology.

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: AMH and AMHR2 genetic variants in Chinese women with primary ovarian insufficiency and normal age at natural menopause. Qin C et al. (2015) The aim of this study was to investigate the role of the anti-Müllerian hormone (AMH) signalling pathway in the pathophysiology of idiopathic primary ovarian insufficiency (POI) and age at natural menopause (ANM) using a genetic approach. DNA sequencing was used to detect the genotype distribution and allele frequency of the genes AMH and AMH receptor II (AMHR2) in 120 cases of idiopathic POI and 120 normal-ANM women. Fourteen sequence variants of AMHR2, including 10 novel variants, were identified. Two novel exonic missense variants were p.I209N and p.L354F. The missense variant p.I209N, which is conserved in different species, was predicted to have functional and structural impacts on the AMHR2 protein. The clinical significance of one additional variant (p.L354F) remains arguable pending functional studies. The genotype frequencies of AMH and AMHR2 were similar in distribution for POI patients and normal-ANM women. These findings suggest that POI patients and normal-ANM women in China share AMH and AMHR2 genetic variants. The AMH signalling pathway associated with ANM also may contribute to POI. //////////////////

Species: mouse
Mutation name:
type: null mutation
fertility: fertile
Comment: Control of primordial follicle recruitment by anti-Müllerian hormone in the mouse ovary. Durlinger AL et al. (1999) The dimeric glycoprotein anti-Müllerian hormone (AMH) is a member of the transforming growth factor-beta superfamily of growth and differentiation factors. During male fetal sex differentiation, AMH is produced by Sertoli cells and induces degeneration of the Müllerian ducts, which form the anlagen of part of the internal female genital system. In females, AMH is produced by the ovary, but only postnatally. The function of AMH in the ovary is, however, still unknown. Female AMH null mice were reported to be fertile, with normal litter size, but this does not exclude a more subtle function for ovarian AMH. To investigate the function of AMH in the ovary, the complete follicle population was determined in AMH null mice, in mice heterozygous for the AMH null mutation, and in wild-type mice of different ages: 25 days, 4 months, and 13 months. In the present study we found that ovaries of 25-day- and 4-month-old AMH null females, compared to those of wild-type females, contain more preantral and small antral follicles. In addition, in 4- and 13-month-old AMH null females, smaller numbers of primordial follicles were found. Actually, in 13-month-old AMH null females, almost no primordial follicles could be detected, coinciding with a reduced number of preantral and small antral follicles in these females. In almost all females heterozygous for the AMH null mutation the number of follicles fell in between the numbers found in wild-type and AMH null females. In 4-month-old AMH null females serum inhibin levels were higher and FSH levels were lower compared to those in wild-type females. In contrast, inhibin levels were lower in 13-month-old AMH null females, and FSH levels were unchanged compared to those in wild-type females. Furthermore, the weight of the ovaries was twice as high in the 4-month-old AMH null females as in age-matched wild-type females. We conclude that AMH plays an important role in primordial follicle recruitment, such that more primordial follicles are recruited in AMH null mice than in wild-type mice; the mice heterozygous for the AMH null mutation take an in-between position. Consequently, the ovaries of AMH null females and those of females heterozygous for the AMH null mutation will show a relatively early depletion of their stock of primordial follicles. The female AMH null mouse may thus provide a useful model to study regulation of primordial follicle recruitment and the relation between follicular dynamics and ovarian aging.//////////////////