A novel AMH variant at the prehelix loop impairs the binding to AMHR2 and causes persistent Mullerian duct syndrome.
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ABSTRACT:
SUBMITTER: Du Q
PROVIDER: S-EPMC10919425 | biostudies-literature | 2023 Oct
REPOSITORIES: biostudies-literature
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A novel AMH variant at the prehelix loop impairs the binding to AMHR2 and causes persistent Müllerian duct syndrome.
Du Qiang Q Qiu Chuang C Zhang Yuan-Yuan YY Shang Xue-Jun XJ Liu Xiao-Liang XL
Asian journal of andrology 20231024 2
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Project description: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.
| S-EPMC8774887 | biostudies-literature
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
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
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
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
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
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
Project description:Persistent Mullerian duct syndrome (PMDS) is a rare syndrome and sometimes the cause of a common problem in paediatric and surgical practice, namely undescended testes. PMDS is a recessive disease in which there is a defect in anti-Mullerian hormone secretion or receptor activity resulting in persistence of Mullerian structures such as a uterus or fallopian tubes with otherwise normal virilisation. Here the authors present a case of a 1½-year-old boy who was referred to their hospital because of unilateral cryptorchidism. During laparoscopic surgery, two gonads were present joined together by a uterus-like structure. Additional investigations showed a normal male karyotype and biopsies of the gonads revealed infantile testis parenchyma making the diagnosis PMDS likely.
| S-EPMC3534258 | biostudies-other
Project description:PurposeThe purpose of this paper is to determine whether there is a correlation between polymorphisms in the growth differentiation factor-9 (GDF-9) gene and anti-Müllerian hormone (AMH) gene and its receptor, AMHR2, and endometriosis-associated infertility.MethodsThis is a case-control study to evaluate whether there is a correlation between polymorphisms in the GDF-9 gene (SNPs determined by direct sequencing), AMH gene, AMHR2 (both SNPs determined by genotyping using TaqMan Allelic Discrimination), and endometriosis-associated infertility. The study included 74 infertile women with endometriosis and 70 fertile women (tubal ligation) as a control group.ResultsPatient age and the mean FSH levels were similar between the infertile with endometriosis and fertile without endometriosis groups. The frequency of genotypes between the groups for GDF-9 gene polymorphisms did not show statistical significance, nor did the AMHR2 gene polymorphism. However, the AMH gene polymorphism did show statistical significance, relating the polymorphic allele with infertility in endometriosis.ConclusionsWe demonstrate that an SNP in the AMH gene is associated with infertility in endometriosis, whereas several SNPs in the GDF-9 gene and the - 482A G SNP in the AMHR2 gene were found to be unrelated.
| S-EPMC5714819 | biostudies-literature
Project description:IntroductionPersistent Mullerian duct syndrome (PMDS) is a genetic disorder characterized by the persistence of Mullerian structures of fallopian tubes, uterus, and upper two-thirds of the vagina in a normal XY male. It is a rare genetic disorder that has been reported less than two hundred times. More rarely it may be seen in association with transverse testicular ectopia (TTE).Presentation of casesFour patients presented with swelling in the inguinal region and undescended testes. Pre-op ultrasound was done on three of these patients and it showed a hernia with testes inside the hernial sac. Hernia surgery was planned for these patients. One patient presented with a complaint of bilateral cryptorchidism that prompted laparoscopic exploration. In all five patients, on surgical exploration, Mullerian derivatives i.e., fallopian tubes, uterus, and vagina were found in the abdomen. Hernia surgery was done and Mullerian structures were excised. For undescended testes, patients had orchiopexy or orchidectomy depending on their respective age group.DiscussionPMDS is caused by failure of production of Mullerian inhibiting substance. Mullerian structures other than causing inguinal hernia are also at risk of malignant transformation, which is the most important significance of this condition. In light of the risk of malignant transformation, Mullerian structures must be excised.ConclusionTo prevent the risk of malignant transformation in PMDS, the Mullerian structures must be excised. If PMDS is associated with TTE, orchiopexy must be done for pediatric patients and orchidectomy for adult patients.
| S-EPMC9403288 | biostudies-literature