Persistent Müllerian duct syndrome associated with genetic defects in the regulatory subunit of myosin phosphatase.

Study Question: Can mutations of genes other than AMH or AMHR2, namely PPP1R12A coding myosin phosphatase, lead to persistent Müllerian duct syndrome (PMDS)?

Summary Answer: The detection of PPP1R12A truncation mutations in five cases of PMDS suggests that myosin phosphatase is involved in Müllerian regression, independently of the anti-Müllerian hormone (AMH) signaling cascade.

What Is Known Already: Mutations of AMH and AMHR2 are detectable in an overwhelming majority of PMDS patients but in 10% of cases, both genes are apparently normal, suggesting that other genes may be involved.

Study Design, Size, Duration: DNA samples from 39 PMDS patients collected from 1990 to present, in which Sanger sequencing had failed to detect biallelic AMH or AMHR2 mutations, were screened by massive parallel sequencing.

Genetics of anti-Müllerian hormone and its signaling pathway.

Anti-Müllerian hormone (AMH) is a member of the TGF-β family produced essentially by the supporting somatic cells of the testis. Initially known for its inhibiting role upon the development of female internal organs, AMH has been shown to exert many other effects namely upon germ cells. Circulating AMH reflects the ovarian reserve of young developing follicles and is used to evaluate the fertility potential in assisted reproduction.

What Does AMH Tell Us in Pediatric Disorders of Sex Development?

Disorders of sex development (DSD) are conditions where genetic, gonadal, and/or internal/external genital sexes are discordant. In many cases, serum testosterone determination is insufficient for the differential diagnosis. Anti-Müllerian hormone (AMH), a glycoprotein hormone produced in large amounts by immature testicular Sertoli cells, may be an extremely helpful parameter.

Persistent Müllerian duct syndrome due to anti-Müllerian hormone receptor 2 microdeletions: a diagnostic challenge.

The persistent Müllerian duct syndrome (PMDS) is defined by the persistence of Müllerian derivatives in an otherwise normally virilized 46,XY male. It is usually caused by mutations in either the anti-Müllerian hormone (AMH) or AMH receptor type 2 (AMHR2) genes. We report the first cases of PMDS resulting from a microdeletion of the chromosomal region 12q13.

Persistent Müllerian duct syndrome: an update.

Male sex differentiation is driven by two hormones, testosterone and anti-Müllerian hormone (AMH), responsible for regression of Müllerian ducts in male fetuses. Mutations inactivating AMH or AMH receptor type 2 (AMHR2) are responsible for persistent Müllerian duct syndrome (PMDS) in otherwise normally virilised 46,XY males. This review is based on published cases, including 157 personal ones.

A mutation inactivating the distal SF1 binding site on the human anti-Müllerian hormone promoter causes persistent Müllerian duct syndrome.

The persistent Müllerian duct syndrome (PMDS) is a 46,XY disorder of sexual development characterized by the persistence of Müllerian duct derivatives, uterus and tubes, in otherwise normally masculinized males. The condition, transmitted as a recessive autosomal trait, is usually due to mutations in either the anti-Müllerian hormone (AMH) gene or its main receptor. Many variants of these genes have been described, all targeting the coding sequences.

WOMEN IN REPRODUCTIVE SCIENCE: Anti-Müllerian hormone: a look back and ahead.

Anti-Müllerian hormone (AMH) is a member of the TGF-β family secreted by immature Sertoli cells and by granulosa cells of growing ovarian follicles. In males, it induces the regression of fetal Müllerian ducts and represses androgen synthesis through receptors located on the Leydig cell membrane. In female mice, AMH inhibits primary follicle recruitment and sensitivity to FSH.

The Persistent Müllerian Duct Syndrome: An Update Based Upon a Personal Experience of 157 Cases.

Male sex differentiation is driven by 2 hormones, testosterone and anti-müllerian hormone (AMH), responsible for the regression of müllerian ducts in male fetuses. Mutations inactivating AMH or its receptor AMHRII lead to the persistent müllerian duct syndrome (PMDS) in otherwise normally virilized 46,XY males. Our objective was to review the clinical, anatomical, and molecular features of PMDS based upon a review of the literature and upon 157 personal cases.

Target-depth estimation in active sonar: Cramer-Rao bounds for a bilinear sound-speed profile.

This paper develops a localization method to estimate the depth of a target in the context of active sonar, at long ranges. The target depth is tactical information for both strategy and classification purposes. The Cramer-Rao lower bounds for the target position as range and depth are derived for a bilinear profile.

The BOC ELISA, a ruminant-specific AMH immunoassay, improves the determination of plasma AMH concentration and its correlation with embryo production in cattle.

Plasma anti-Müllerian hormone (AMH) concentrations have been recently found to be predictive of the number of embryos recovered after FSH superovulatory treatment in the cow. However, the sensitivity of the Active Müllerian-inhibiting substance/AMH ELISA (ref. 10-14400; DSL-Beckman-Coulter) used to make these measurements in bovine plasma samples is low because it was developed to measure human AMH levels.

Anti-müllerian hormone: a valuable addition to the toolbox of the pediatric endocrinologist.

Anti-Müllerian hormone (AMH), secreted by immature Sertoli cells, provokes the regression of male fetal Müllerian ducts. FSH stimulates AMH production; during puberty, AMH is downregulated by intratesticular testosterone and meiotic germ cells. In boys, AMH determination is useful in the clinical setting.

Testicular anti-Müllerian hormone: clinical applications in DSD.

Male fetal sexual differentiation of the genitalia is driven by Leydig cell-secreted androgens and Sertoli cell-secreted anti-Müllerian hormone (AMH). Disorders of sex development (DSD) may be due to abnormal morphogenesis of genital primordia or to defective testicular hormone secretion or action. In dysgenetic DSD, due to an early fetal-onset primary hypogonadism affecting Leydig and Sertoli cells, the fetal gonads are incapable of producing normal levels of androgens and AMH.

Advice on the management of ambiguous genitalia to a young endocrinologist from experienced clinicians.

The birth of a child with ambiguous genitalia is a challenging and distressing event for the family and physician and one with life-long consequences. Most disorders of sexual differentiation (DSD) associated with ambiguous genitalia are the result either of inappropriate virilization of girls or incomplete virilization of boys. It is important to establish a diagnosis as soon as possible, for psychological, social, and medical reasons, particularly for recognizing accompanying life-threatening disorders such as the salt-losing form of congenital adrenal hyperplasia.

Mutations of the AMH type II receptor in two extended families with persistent Müllerian duct syndrome: lack of phenotype/genotype correlation.

Our goal was to compare phenotype and genotype in two extended Middle-Eastern families affected by persistent Müllerian duct syndrome due to mutations of the type II anti-Müllerian hormone receptor (AMHR-II). The first, consanguineous, family consisted of 6 boys and 2 girls, the second consisted of 4 girls and 2 boys. In family I, 4 boys and 1 girl were homozygous for a stop mutation in the 9th exon of AMHR-II, removing part of the intracellular domain of the protein.

Regional variations in the management of testicular or ovotesticular disorders of sex development.

Disorders of sex development arise in parts of the world with different socio-economic and cultural characteristics. We wished to determine the regional variations in the management of these conditions. A questionnaire was e-mailed to the 650 members of the European Society for Paediatric Endocrinology (ESPE), an international society with a mainly European membership but which also includes professionals from other continents.

SOX9 and SF1 are involved in cyclic AMP-mediated upregulation of anti-Mullerian gene expression in the testicular prepubertal Sertoli cell line SMAT1.

In Sertoli cells, anti-Müllerian hormone (AMH) expression is upregulated by FSH via cyclic AMP (cAMP), although no classical cAMP response elements exist in the AMH promoter. The response to cAMP involves NF-κB and AP2; however, targeted mutagenesis of their binding sites in the AMH promoter do not completely abolish the response. In this work we assessed whether SOX9, SF1, GATA4, and AP1 might represent alternative pathways involved in cAMP-mediated AMH upregulation, using real-time RT-PCR (qPCR), targeted mutagenesis, luciferase assays, and immunocytochemistry in the Sertoli cell line SMAT1.

FSH and its second messenger cAMP stimulate the transcription of human anti-Müllerian hormone in cultured granulosa cells.

Anti-Müllerian hormone (AMH), also called Müllerian-inhibiting substance, a member of the TGF-ß family, is responsible for the regression of Müllerian ducts in the male fetus. In females, AMH is synthesized by granulosa cells of preantral and small antral follicles, and production wanes at later stages of follicle maturation. Using RT-PCR in luteal granulosa cells in primary culture and reporter gene techniques in the KK1 granulosa cell line, we show that FSH and cAMP enhance AMH transcription, and LH has an additive effect.

Source motion detection, estimation, and compensation for underwater acoustics inversion by wideband ambiguity lag-Doppler filtering.

Acoustic channel properties in a shallow water environment with moving source and receiver are difficult to investigate. In fact, when the source-receiver relative position changes, the underwater environment causes multipath and Doppler scale changes on the transmitted signal over low-to-medium frequencies (300 Hz-20 kHz). This is the result of a combination of multiple paths propagation, source and receiver motions, as well as sea surface motion or water column fast changes.

Processing of anti-mullerian hormone regulates receptor activation by a mechanism distinct from TGF-beta.

TGF-β family ligands are translated as prepropeptide precursors and are processed into mature C-terminal dimers that signal by assembling a serine/threonine kinase receptor complex containing type I and II components. Many TGF-β ligands are secreted in a latent form that cannot bind their receptor, due to the pro-region remaining associated with the mature ligand in a noncovalent complex after proteolytic cleavage. Here we show that anti-Müllerian hormone (AMH), a TGF-β family ligand involved in reproductive development, must be cleaved to bind its type II receptor (AMHRII), but dissociation of the pro-region from the mature C-terminal dimer is not required for this initial interaction.

Early expression of the androgen receptor in the Sertoli cells of a marsupial coincides with downregulation of anti-Müllerian hormone at the time of urogenital virilization.

Anti-Müllerian hormone (AMH), responsible for the regression of Müllerian ducts, is strongly expressed by eutherian fetal and postnatal Sertoli cells. Both AMH and testosterone levels are high during the period of fetal reproductive tract virilization which occurs largely in utero in eutherian mammals. Taking advantage of the fact that differentiation of the urogenital tract occurs after birth in marsupials, we studied the ontogeny and regulation of AMH in the tammar wallaby testis and related it to the expression of the androgen receptor in Sertoli cells.

On the consideration of motion effects in the computation of impulse response for underwater acoustics inversion.

The estimation of the impulse response (IR) of a propagation channel may be of great interest for a large number of underwater applications: underwater communications, sonar detection and localization, marine mammal monitoring, etc. It quantifies the distortions of the transmitted signal in the underwater channel and enables geoacoustic inversion. The propagating signal is usually subject to additional and undesirable distortions due to the motion of the transmitter-channel-receiver configuration.

Natural mutations of the anti-Mullerian hormone type II receptor found in persistent Mullerian duct syndrome affect ligand binding, signal transduction and cellular transport.

The anti-Müllerian hormone type II (AMHRII) receptor is the primary receptor for anti-Müllerian hormone (AMH), a protein produced by Sertoli cells and responsible for the regression of the Müllerian duct in males. AMHRII is a membrane protein containing an N-terminal extracellular domain (ECD) that binds AMH, a transmembrane domain, and an intracellular domain with serine/threonine kinase activity. Mutations in the AMHRII gene lead to persistent Müllerian duct syndrome in human males.