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Identification of AMH and AMHR2 Variants Led to the Diagnosis of Persistent Mullerian Duct Syndrome in Three Cases.

ABSTRACT: Persistent Müllerian duct syndrome (PMDS) is a rare autosomal recessive disorder of sexual development in males, defined by the presence of Müllerian remnants with otherwise normal sexual differentiation. Mutations in anti-Müllerian hormone (AMH) and AMH receptor type 2 (AMHR2) genes are the main causes of PMDS. In this study, we performed molecular genetic analysis of 11 unrelated cryptorchidism patients using whole-exome sequencing and classified the variants. Three of the 11 patients had biallelic mutations in AMH or AMHR2. Case 1 carried a homozygous 4-bp deletion; c.321_324del:p.Q109Lfs*29 in exon 1 of AMH (NM_000479 transcript), which is a frameshift mutation, leading to the loss of function of AMH. Case 2 carried compound heterozygous mutations; c.494_502del (p.I165_A168delinsT) in exon 4 and g.6147C>A of AMHR2 (NM_001164690 transcript). Case 3 carried compound heterozygous mutations; c.G1168A (p.E390K) in exon 9 and c.A1315G (p.M439V) in exon 10 of AMHR2 (NM_001164690 transcript). All three patients were admitted due to azoospermia- and oligospermia-caused infertility. They were furtherly diagnosed with PMDS, as pelvic magnetic resonance imaging revealed the presence of Müllerian remnants. Our study suggests that PMDS and genetic analysis should be considered during the differential diagnosis of cryptorchidism.

SUBMITTER: Liu Y

PROVIDER: S-EPMC8774887 | biostudies-literature |

REPOSITORIES: biostudies-literature

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A novel AMH variant at the prehelix loop impairs the binding to AMHR2 and causes persistent Mullerian duct syndrome.

Project description: Not available

| S-EPMC10919425 | biostudies-literature

Two novel AMHR2 gene variants in monozygotic twins with persistent Mullerian duct syndrome: A case report and functional study.

Project description:BackgroundPersistent Müllerian duct syndrome (PMDS) is an autosomal recessive congenital abnormality in which Müllerian derivatives, uterus, cervix, upper two-thirds of the vagina, and fallopian tubes persist in otherwise normally virilized males. Mutations in anti-Müllerian hormone (AMH) and AMH receptor type II (AMHR2) genes have been identified as causative. However, functional experimental analysis of AMHR2 or AMH variants that cause PMDS is still lacking.Materials and methodsA Chinese Han family affected by PMDS was identified. To assess the history and clinical manifestations of PMDS, physical, operational, ultrasonographical, pathological, and other examinations were performed on family members. The variant screening was conducted using trio whole-exome sequencing (trio WES) and Sanger sequencing. Complementation-based NanoLuciferase Binary Technology (NanoBiT) was used to examine the interaction between AMH and AMHR2 variants in vivo. The effect of the two variants on the transcriptional activity of the TGFβ/BMP pathway was evaluated using a luciferase assay.ResultsClassic phenotypic manifestations of PMDS in a pair of identical twins were described and confirmed by genetic sequence analysis. Molecular studies revealed two novel variants c.118G > C [p.(Gly40Arg)], c.1222G > C [p.(Ala408Pro)] in the AMHR2 gene. The AMHR2 p.Gly40Arg variant reduces its ability to bind to AMH, while the p.Ala408Pro variant alters the kinase domain structure. Both variants significantly reduce TGFβ/BMP signaling.ConclusionTwo missense AMHR2 variants associated with PMDS were identified. These findings provide novel insights toward better clinical evaluation and further understanding of the molecular basis of PMDS.

| S-EPMC9356563 | biostudies-literature

A novel mutation of AMHR2 in two brothers with persistent Mullerian duct syndrome and their intracytoplasmic sperm injection outcome.

Project description:BackgroundPersistent Müllerian duct syndrome (PMDS) is defined as the presence of Müllerian duct derivatives in an otherwise normally virilized 46, XY male. It is usually caused by homozygous or compound heterozygous mutations in either the anti-Müllerian hormone (AMH) or AMH receptor type 2 (AMHR2) genes. The main purpose of the study is to determine the novel mutations of AMHR2 in PMDS patients and their intracytoplasmic sperm injection outcomes (ICSI).MethodsWhole-exome sequencing (WES) was carried out. Sanger sequencing was used to detect mutations in AMHR2. The pathogenicity of the identified variant and its possible effects on the protein were evaluated with in silico tools. The expression level of AMHR2 was determined by Western blotting. The spermatogenic function was evaluated by testicular sperm aspiration and histopathologic examination. The ICSI outcomes were recorded.ResultsWe present two brothers with a history of bilateral cryptorchidism with orchidopexy and infertility due to azoospermia. A novel compound heterozygous mutation of c.1219C>T [p.R407X] and c.1387C>T [p.R463C] in exons 9 and 10 of AMHR2 (NM_020547.2) was detected by whole-exome sequencing (WES). Spermatozoon could be retrieved from the two patients by testicular aspiration following intracytoplasmic sperm injection (ICSI) due to azoospermia. Finally, patient 1 had two healthy boys and patient 2 failed to conceive after three ICSI attempts.ConclusionThe spermatozoa could obtain from PMDS patients due to azoospermia. For patients with bilateral cryptorchidism, PMDS should be included in the differential diagnosis and that genetic counseling needs to be considered when they seek reproductive help.

| S-EPMC8580084 | biostudies-literature

Prevalence of the AMHR2 mutation in Miniature Schnauzers and genetic investigation of a Belgian Malinois with persistent Mullerian duct syndrome.

Project description:Persistent Müllerian duct syndrome (PMDS) is a sex-limited disorder in which males develop portions of the female reproductive tract. Important consequences of PMDS are cryptorchidism and its sequelae of infertility and increased risk of testicular cancer. Anti-Müllerian hormone (AMH) and its receptor (AMHR2) induce the regression of the Müllerian ducts in male embryos. In Miniature Schnauzer dogs, the genetic basis has been identified as an autosomal recessive nonsense mutation in AMHR2, but the allele frequency of the mutation is unknown. Thus, the primary objective of this study was to estimate the prevalence of the AMHR2 mutation in North American Miniature Schnauzers, in order to ascertain the value of genetic testing in this breed. An additional objective was to determine whether mutations in AMH or AMHR2 were responsible for PMDS in a Belgian Malinois; this would aid development of a genetic test for the Belgian Malinois breed. Genomic DNA from 216 Miniature Schnauzers (including one known PMDS case) was genotyped for the AMHR2 mutation, and DNA from a single PMDS-affected Belgian Malinois was sequenced for all coding exons of AMH and AMHR2. The Miniature Schnauzer cohort had an AMHR2 mutation allele frequency of 0.16 and a carrier genotypic frequency of 0.27. The genetic basis for PMDS in the Belgian Malinois was not determined, as no coding or splicing mutations were identified in either AMH or AMHR2. These findings support a benefit to AMHR2 mutation testing Miniature Schnauzers used for breeding or with cryptorchidism.

| S-EPMC5847425 | biostudies-literature

Surgical management and molecular diagnosis of persistent Mullerian duct syndrome in Chinese patients.

Project description:Persistent Müllerian duct syndrome (PMDS) is a rare clinically and genetically overlapping disorder caused by mutations in the anti-Müllerian hormone (AMH) gene or the anti-Müllerian hormone receptor type 2 (AMHR2) gene. Affected individuals present uterus and tubes in normally virilized males and are discovered unexpectedly during other surgeries. Since it is rare and complex, a definitive clinical diagnosis can be missed, and there are no guidelines regarding how to deal with the uterus. In the present study, exome sequencing and Sanger verification were performed for causal variants in 12 PMDS patients. Preoperative diagnoses were made by positive exome sequencing in 8 patients. Of them, 7 patients evoked on the basis of ultrasound indicating bilateral testes on the same side of the body. Twelve different AMH variants (2 frameshift/nonsense, 1 deletion, 8 missense, and 1 in-frame) in 9 patients and 6 different AMHR2 variants (5 missense and 1 splicing) in 3 patients were identified. Seven variants were classified as "pathogenic" or "likely pathogenic", and 4 of them were novel. All but two patients with AMH defects showed low serum AMH concentrations, but all patients with AMHR2 defects showed elevated AMH levels. During surgery, an abnormal vas deferens was observed in half of the patients. Eight patients underwent orchidopexy with uterine preservation. Of them, 2 patients presented complications including irreducible cryptorchidism, and 3 patients developed Müllerian remnant cysts. Three patients underwent subtotal hysterectomy. Of them, one patient had complication of injury to the vas deferens, and one had hemorrhage after operation. This is the first report of PMDS involving a large Chinese population. The present study not only expands the variation spectrum but also provides clinical experience about the management of the uterus.

| S-EPMC8788598 | biostudies-literature

Mutational Analysis of the Putative Anti-Mullerian Hormone (AMH) Binding Interface on its Type II Receptor, AMHR2.

Project description:Anti-Müllerian hormone (AMH) or Müllerian inhibiting substance is a unique member of the TGF-β family responsible for development and differentiation of the reproductive system. AMH signals through its own dedicated type II receptor, anti-Müllerian hormone receptor type II (AMHR2), providing an exclusive ligand-receptor pair within the broader TGF-β family. In this study, we used previous structural information to derive a model of AMH bound to AMHR2 to guide mutagenesis studies to identify receptor residues important for AMH signaling. Nonconserved mutations were introduced in AMHR2 and characterized in an AMH-responsive cell-based luciferase assay and native PAGE. Collectively, our results identified several residues important for AMH signaling within the putative ligand binding interface of AMHR2. Our results show that AMH engages AMHR2 at a similar interface to how activin and BMP class ligands bind the type II receptor, ACVR2B; however, there are significant molecular differences at the ligand interface of these 2 receptors, where ACVR2B is mostly hydrophobic and AMHR2 is predominately charged. Overall, this study shows that although the location of ligand binding on the receptor is similar to ACVR2A, ACVR2B, and BMPR2; AMHR2 uses unique ligand-receptor interactions to impart specificity for AMH.

| S-EPMC7286617 | biostudies-literature

Persistent Mullerian Duct Syndrome: A Single-Center Experience.

Project description:Context:Persistent Mullerian duct syndrome (PMDS) is a rare disorder. It is a type of male pseudohermaphroditism, usually presenting as "Hernia Uteri Inguinalis". Aims:This study aims to present our experience of PMDS, over a 7-year period. Settings and Design:Our center is a tertiary care facility, situated in Tamil Nadu, a southern state of India. Subjects and Methods:This is a retrospective study. The study period was from 2007 to 2015. Seven cases presented during that period. The difficulties in diagnosis, treatment options discussed, along with a review of literature are presented. Results:Seven cases of PMDS presented over 8 years. Only four were diagnosed preoperatively. Mullerian remnants were excised in five cases. Conclusions:PMDS is rare. Orchiopexy should be the goal of treatment.

| S-EPMC6182940 | biostudies-other

Interactions between genetic variants in AMH and AMHR2 may modify age at natural menopause.

Project description:The onset of menopause has important implications on women's fertility and health. We previously identified genetic variants in genes involved in initial follicle recruitment as potential modifiers of age at natural menopause. The objective of this study was to extend our previous study, by searching for pairwise interactions between tagging single nucleotide polymorphisms (tSNPs) in the 5 genes previously selected (AMH, AMHR2, BMP15, FOXL2, GDF9). We performed a cross-sectional study among 3445 women with a natural menopause participating in the Prospect-EPIC study, a population-based prospective cohort study, initiated between 1993 and 1997. Based on the model-based multifactor dimensionality reduction (MB-MDR) test with a permutation-based maxT correction for multiple testing, we found a statistically significant interaction between rs10407022 in AMH and rs11170547 in AMHR2 (p?=?0.019) associated with age at natural menopause. Rs10407022 did not have a statistically significant main effect. However, rs10407022 is an eQTL SNP that has been shown to influence mRNA expression levels in lymphoblastoid cell lines. This study provides additional insights into the genetic background of age at natural menopause and suggests a role of the AMH signaling pathway in the onset of natural menopause. However, these results remain suggestive and replication by independent studies is necessary.

| S-EPMC3609726 | biostudies-literature

Correlation between three assay systems for anti-Mullerian hormone (AMH) determination.

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| S-EPMC3528883 | biostudies-literature

Persistent Mullerian duct syndrome with transverse testicular ectopia: A case report.

Project description:Persistent Mullerian duct syndrome (PMDS) is a rare entity of internal male pseudohermaphroditism. Transverse testicular ectopia (TTE) is the condition in which one testis moves to the other side and both testes pass the same inguinal canal. The combination of PMDS with TTE is rarer. Here, we present a case a phenotype male with left inguinal hernia and right undescended testis. On exploration of left inguinal region, uterus like tissue with its tubal structures were found. Both testes were in same side, one in left inguinal region and the other in the left scrotum.

| S-EPMC6503297 | biostudies-literature

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