Biomedical subjects

N Josso

Publications and source records attributed to N Josso.

At least 37 records · Page 2Linked to original sources

PubMed1996

Mutant isoforms of the anti-Müllerian hormone type II receptor are not expressed at the cell membrane.

Anti-Müllerian hormone, a member of the transforming growth factor beta superfamily, produces early regression of Müllerian ducts in the male fetus through binding to a serine/threonine kinase receptor, homologous to type II receptors of the transforming growth factor beta (TGF-beta) family. A splice mutation of this receptor, described in a patient with abnormal retention of Müllerian derivatives, generates two mutant isoforms, one lacking the second exon and the other bearing an insertion of 12 bases between exons 2 and 3. Using hemagglutinin-tagged recombinant receptors, we have visualized wild type and mutant receptors in COS cells by Western blotting and immunoprecipitation. The 82-kDa, endoglycosidase H-insensitive, mature form of the wild type receptor is reduced to 68 kDa by N-glycosidase F treatment. Mutant receptor isoforms, 73 and 63 kDa for the long and short form, respectively, are sensitive to endoglycosidase H, suggesting that they are retained in the endoplasmic reticulum. Indeed, only the wild type receptor was expressed on the cell surface and bound iodinated anti-Müllerian hormone. These results provide a biological explanation for the failure of the mutant receptor to induce Müllerian regression.

Alternative Splicing↗

PubMed1996

Genetic analysis of the Müllerian-inhibiting substance signal transduction pathway in mammalian sexual differentiation.

Müllerian-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 Müllerian 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 Müllerian 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.

Alleles↗

PubMed1996

Cloning and expression of the chick anti-Müllerian hormone gene.

Müllerian duct regression in male embryos is due to early production by fetal Sertoli cells of anti-Müllerian hormone, a homodimeric protein of the transforming growth factor- beta superfamily. In mammals, both female Müllerian ducts develop into the uterus and Fallopian tubes, whereas in birds, the right oviduct does not develop. To gain insight into sex differentiation in birds, we have cloned the cDNA for chick anti-Müllerian hormone using antibodies raised against the partially purified protein. Expression cloning was required because of the lack of cross-hybridization between mammalian and chick anti-Müllerian hormone DNA. The chick DNA and protein are significantly longer, due to insertions that abolish nucleotide homology, except in the cDNA coding for the C-terminal, bioactive part of the protein. Nevertheless, the general structure of the gene, sequenced from the transcription initiation to the polyadenylation site, and the main features of the protein are conserved between the chick and mammals. The chick anti-Müllerian hormone gene is expressed at high levels in Sertoli cells of the embryonic testes and in lower amounts in both ovaries, higher levels being reached on the left side after 10 days of incubation.

Amino Acid Sequence↗

PubMed1996

Antimüllerian hormone as a serum marker of granulosa cell tumorsof the ovary: comparative study with serum alpha-inhibin and estradiol.

OBJECTIVE: Our purpose was to evaluate serum antimüllerian hormone as a marker for granulosa cell tumors. STUDY DESIGN: Serum antimüllerian hormone concentrations were determined in 16 patients with an adult-type granulosa cell tumor; in female patients with ovarian adenocarcinoma, benign ovarian cysts, or extraovarian cancers; and in normal premenopausal and postmenopausal women. Serum antimüllerian hormone, alpha-inhibin, and estradiol levels were compared in 10 patients with a granulosa cell tumor during 6 to 47 months of follow-up. RESULTS: Serum antimüllerian hormone was undetectable in normal postmenopausal women and was <5 micrograms/L in premenopausal women. Normal serum levels were found in patients with ovarian cancers or cysts or with extraovarian cancers. Levels were between 6.8 and 117.9 microg/L in eight of nine patients with a progressive granulosa cell tumor. In the remaining case antimüllerian hormone, alpha-inhibin and estradiol concentrations were normal. Serum antimüllerian hormone and alpha-inhibin levels became elevated at least 11 months before the recurrence was clinically detectable. During clinical remission serum antimullerian hormone, beta-inhibin, and estradiol were normal in most cases. CONCLUSION: Serum antimüllerian hormone is a sensitive, specific, reliable marker of adult-type granulosa cell tumors and is useful to evaluate the efficacy of treatment and to detect recurrences early.

Adolescent↗

PubMed1996

A 27 base-pair deletion of the anti-müllerian type II receptor gene is the most common cause of the persistent müllerian duct syndrome.

The persistent müllerian duct syndrome, characterized by the lack of regression of müllerian derivatives, uterus and tubes in otherwise normally masculinized males, is a genetically transmitted disorder implicating either anti-müllerian hormone (AMH), a member of the transforming growth factor-beta superfamily, or its type II receptor, a serine/threonine kinase homologous to the receptors of other members of the transforming growth factor-beta superfamily. We have now performed molecular studies in a total of 38 families. The basis of the condition, namely 16 AMH and 16 AMH receptor mutations, was identified in 32 families. The type of genetic defect could be predicted from the level of serum AMH which is very low or undetectable in patients with AMH mutations and at the upper limit of normal in receptor mutations. Whereas AMH mutations are extremely diverse, patients from 10 out of 16 families with receptor mutations had a 27 bp deletion in exon 10 on at least one allele. This deletion is thus implicated in approximately 25% of patients with persistent müllerian duct syndrome. All AMH and AMH receptor mutations were consistent with an autosomal recessive mode of transmission.

Amino Acid Sequence↗

PubMed1996

Genetic mechanisms of sex differentiation.

Cloning of the SRY sex-determining locus on the Y chromosome has stimulated research on the genetic mechanisms of sex determination. It now appears that SRY is not the only gene required for testicular differentiation; X-linked and autosomal genes are also important. In parallel, mutations of genes involved in somatic sex differentiation shed light on the mechanisms involved in testis-dependent events.

Gonads↗

PubMed1996

Regulation of testicular anti-M ullerian hormone secretion.

Anti-Müllerian hormone (AMH) is a glycoprotein secreted by Sertoli cells from the time of testicular differentiation and is responsible for the regression of Müllerian ducts in the male fetus. The chronology of AMH expression is very important because Müllerian ducts lose their responsiveness a few days after AMH secretion begins, which suggests that the AMH gene is under precise transcriptional control. Steroidogenic factor 1 (SF-1) is the only transcriptional regulator with demonstrated action on AMH expression. Although necessary for AMH expression, SF-1 alone is not sufficient to induce AMH transcription. SRY expression is turned on in Sertoli cells just before AMH expression is initiated, but the effective implication of SRY in AMH regulation remains unclear. During puberty, AMH expression is regulated negatively by androgens and declines dramatically in seminiferous tubules with meiotic development. Low serum AMH levels are observed in both central and gonadotropin-independent precocious puberty, which suggests that gonadotropins do not down-regulate AMH at puberty. Serum AMH returns to normal infantile values 3-6 months after treatment. The absence of androgen response elements on the AMH promoter and the slow response to androgen withdrawal suggest that androgen regulation of AMH secretion is indirect. In patients with defects of androgen production or action, serum AMH reaches abnormally high levels in the neonatal and pubertal periods, which suggests a possible stimulatory role for gonadotropins that could be observed only in the absence of suppressive effects of androgens.

Aging↗

PubMed1996

Testicular dysgenesis does not affect expression of anti-müllerian hormone by Sertoli cells in premeiotic seminiferous tubules.

Anti-Müllerian hormone (AMH) immunoreactivity was studied on paraffin sections obtained from archival testicular biopsies of 29 children with intersex disorders and of 22 controls. Strong AMH immunoreactivity was observed in Sertoli cell cytoplasm from 8 fetal weeks until puberty. During pubertal maturation, in both normal and intersex patients, AMH expression was present in premeiotic seminiferous tubules, but was no longer detected in neighboring tubules with meiotic development. AMH immunostaining was abolished in the testis of one patient with persistent Müllerian ducts due to a mutation of the AMH gene, but was conserved in the testes of two patients with mutations of the AMH receptor gene. Testicular dysgenesis usually results in sexual ambiguity, with low testosterone and AMH serum levels and persistence of Müllerian derivatives. AMH immunoreactivity was conserved in premeiotic seminiferous tubules of dysgenetic testes, and also in sex-cord cells of a gonadoblastoma. In patients with asymmetric gonadal differentiation, the streak gonad was AMH-negative. In conclusion, secretion of AMH is a constitutive feature of the immature Sertoli cell and its expression is altered only by mutations of the AMH gene, but not by gonadal dysgenesis. The degree of regression of Müllerian ducts and serum AMH levels reflect the number, not the functional value, of Sertoli cells present in the immature testis.

Adolescent↗

PubMed1996

[Molecular biology of the persistent Müllerian duct syndrome].

The persistent Müllerian duct syndrome, characterized by the presence of uterus and tubes in otherwise normally masculinized 46,XY males, is a familial autosomal recessive disorder due to defects of synthesis or action of anti-Müllerian hormone. We have performed molecular studies in a total of 38 families and we have identified the basis of the condition, namely 16 anti-Müllerian hormone and 16 anti-Müllerian hormone receptor mutations, in 32 families.

Anti-Mullerian Hormone↗

PubMed1995

Testicular degeneration in three patients with the persistent müllerian duct syndrome.

UNLABELLED: The persistent müllerian duct syndrome, characterized by the presence of uterus and tubes in males, is a familial disorder due to defects of synthesis or action of anti-müllerian hormone, a Sertoli cell glycoprotein responsible for the regression of müllerian derivatives in normal male fetuses. Patients are normally virilized and testicular production of testosterone is normal. Both testes may be cryptorchid; alternatively, one may be descended into the inguinal canal or scrotum, together with the müllerian derivatives, a condition known as "hernia uteri inguinalis". We have recently observed three patients affected by the persistent müllerian duct syndrome who experienced progressive degeneration of testicular tissue. In two, functional testicular tissue was still present some months after birth, but deteriorated progressively later. In one patient, testicular tissue was already absent at birth, but the normal virilization of external genitalia indicated that testicular degeneration must have occurred late during fetal life, after the expected time of regression of male müllerian ducts. CONCLUSION: The high incidence of degeneration of testicular tissue in the persistent müllerian duct syndrome could be indirectly linked to anatomical abnormalities which could favour testicular torsion, known to induce testicular regression.

Chronic Disease↗

PubMed1995

Insensitivity to anti-müllerian hormone due to a mutation in the human anti-müllerian hormone receptor.

Anti-Müllerian hormone (AMH) and its receptor are involved in the regression of Müllerian ducts in male fetuses. We have now 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 Müllerian 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.

Alternative Splicing↗

PubMed1995

Ontogeny of reproductive abnormalities induced by deregulation of anti-müllerian hormone expression in transgenic mice.

Anti-müllerian hormone, normally responsible for the regression of müllerian ducts in male fetuses, induces stunting, germ cell loss, and seminiferous tubule formation in ovaries of bovine freemartin fetuses and of transgenic mice, which express the human anti müllerian hormone gene under the control of the metallothionein promoter. Because the latter have been studied only after birth, we undertook a detailed chronological study of their reproductive organs. Müllerian ducts of transgenic female fetuses regressed at the same time as those of normal or transgenic males. Maximal reduction of germ cell number occurred between 16 days postcoitus and birth, when most transgenic oocytes were still in the leptotene stage of the meiotic prophase, whereas normal oocytes had already reached the pachytene phase. Interference with progression of the meiotic prophase and germ cell loss in the fetal ovary are probably responsible for subsequent ovarian regression and retardation of follicle growth. Seminiferous tubule formation was not detectable prior to birth and occurred only rarely in postnatal ovaries. Aromatase activity of fetal transgenic ovaries was decreased, as well as serum concentration of testosterone in adult transgenic males, suggesting that high levels of anti-müllerian hormone may impair Leydig cell steroidogenesis.

Animals↗

PubMed1995

Paediatric applications of anti-müllerian hormone research. 1992 Andrea Prader Lecture.

Anti-müllerian hormone (AMH), a member of the transforming growth factor family also called müllerian-inhibiting substance or factor, is produced by immature Sertoli cells and, in much smaller amounts, by postnatal granulosa cells. Its paediatric applications are essentially diagnostic. Measurement of AMH concentration in serum by an enzyme-linked immunosorbent assay does not require prior gonadal stimulation and is useful to detect the presence of testicular tissue and assess its function before puberty. The assay can easily differentiate between bilateral cryptorchidism and anorchia and discriminates between non-adrenal female pseudohermaphroditism and true hermaphroditism, although in the latter condition, the serum AMH concentration is usually low because of testicular dysgenesis. After puberty, AMH becomes low or undetectable, due to down-regulation of AMH production by testosterone. This does not occur in androgen-insensitive patients. A rare form of male pseudohermaphroditism, the persistent müllerian duct syndrome, characterized by the persistence of a uterus and tubes in otherwise normally virilized males, is due to defects in genes coding for AMH or its receptor. Measurement of serum AMH concentration discriminates between the two aetiological forms of the syndrome.

Anti-Mullerian Hormone↗

PubMed1994

Molecular genetics of the persistent müllerian duct syndrome: a study of 19 families.

A rare form of familial male pseudohermaphroditism, the persistent Müllerian duct syndrome (PMDS) is characterized by persistence of uterus and Fallopian tubes in 46,XY phenotypic males and is ascribed to defects in the synthesis or action of anti-Müllerian hormone (AMH). Biologically, PMDS is heterogeneous: in some cases, bioactive AMH is normally expressed by testicular tissue while, in others, no AMH is produced, suggesting the possibility of an AMH gene mutation, several of which have already been described. Molecular analysis of the AMH gene has now been performed in 21 additional patients and their families. In 6 patients, with normal serum concentration of AMH, the AMH gene was normal or contained only polymorphisms and silent mutations, supporting the hypothesis that the condition is due to end-organ resistance. Nine novel mutations were discovered in the remaining subjects, with low or undetectable levels of serum AMH. These mutations, when present in homozygotes or compound heterozygotes, were associated with the PMDS phenotype, the same mutation never being observed in two different families. The three first exons of the AMH gene appear particularly mutation-prone, although they are less GC rich than the 2 last ones and code for the N-terminal part of the AMH protein, which is not in itself essential to bioactivity.

Anti-Mullerian Hormone↗

PubMed1994

Anti-müllerian hormone in children with androgen insensitivity.

Anti-Müllerian hormone (AMH), also called Müllerian inhibiting substance or factor, is secreted in high amounts by the immature Sertoli cell; it is negatively regulated by testosterone at puberty. In the present study, we measured serum AMH in 20 patients with defects of androgen synthesis or action: 9 with complete androgen insensitivity syndrome, 9 with a partial form, 1 patient with 3 beta-hydroxysteroid dehydrogenase deficiency, and 1 with Leydig cell agenesis. AMH was also determined in 15 control patients with idiopathic male pseudohermaphroditism. The serum AMH concentration was elevated in all testosterone-insensitive or -deficient patients compared with control levels during the first year of life. From 1 yr of age to the onset of puberty, serum AMH levels in patients with androgen insensitivity returned to normal values, but after pubertal development began, AMH levels again rose to extremely high levels in the complete androgen insensitivity syndrome. These results suggest that AMH is negatively regulated by testosterone not only at puberty, but also during the postnatal period. An elevation of serum AMH appears to be an interesting marker of androgen resistance or defect of androgen production in sexually ambiguous male infants.

Adolescent↗

PubMed1994

Cloning, expression, and alternative splicing of the receptor for anti-Müllerian hormone.

Anti-Müllerian hormone, also called Müllerian-inhibiting substance or factor, is a glycoprotein dimer belonging to the transforming growth factor-beta superfamily and synthesized by immature Sertoli cells and postnatal granulosa cells. Anti-Müllerian hormone plays a key role in sex differentiation by inducing the regression of Müllerian ducts in the male fetus. It is also responsible for the stunting and masculinization of fetal ovaries in bovine freemartin fetuses and may be involved in the control of follicular maturation in the postnatal ovary. Using a degenerate probe for a consensus region of the transforming growth factor-beta receptor superfamily to screen a complementary DNA library from rabbit fetal ovaries, we cloned a complementary DNA coding for a transmembrane serine/threonine kinase, which is expressed around the fetal Müllerian duct, in fetal and adult granulosa cells, and in immature Sertoli cells. Two transcripts, generated by alternative splicing of an exon coding for an N-terminal 61-amino acid domain, are strongly expressed in anti-Müllerian hormone target organs and Sertoli cells. The longer, 569-amino acid, isoform binds anti-Müllerian hormone when transiently expressed in COS cells and is believed to encode its functional receptor.

Amino Acid Sequence↗

PubMed1994

[Antimullerian hormone in clinical human applications].

Anti-Müllerian hormone (AMH) is synthesized by immature Sertoli cells and by postnatal granulosa cells. Assay of serum AMH is useful in clinical situations to search for the presence of testicular tissue or to assess its functional value before puberty. At the time of puberty, serum levels of AMH decrease dramatically, a negative correlation has been demonstrated between AMH and testosterone serum levels. AMH assay is also useful in a rare form of male pseudohermaphroditism, characterized by the persistence of uterus and tubes in an otherwise normally virilized patient. AMH levels are undetectable or severely decreased in the case of a mutation of the AMH gene itself. In contrast, the concentration of serum AMH is normal if the syndrome is due to an insensitivity of AMH target organs.

Adolescent↗

PubMed1994

[Persistent müllerian duct syndrome (males with uterus): a pediatric problem].

BACKGROUND: The persistent müllerian duct syndrome (PMDS) is characterized by the persistence of the uterus and Fallopian tubes in otherwise normally virilized boys. Its diagnosis is usually made during a surgical procedure for inguinal hernia or cryptorchidism. We report six recent cases of PMDS, in which we have studied anti-Müllerian hormone (AMH) serum levels. CASE REPORTS AND METHODS: Six boys including three brothers were operated on for cryptorchidism or inguinal hernia. Surgical exploration showed persistence of the uterus and Fallopian tubes in patients having normal 46, XY karyotype and male gonads. The AMH serum levels were measured by Elisa and the AMH gene by single strand conformation polymorphism of PCR products. RESULTS: The three brothers showed a mutation in the AMH gene which leads to the replacement of leucine by proline at position 70 and to a defect in AMH production. In two other patients, serum AMH values were normal, no mutation on the AMH gene was found, and end-organ insensitivity was suggested to explain the persistence of müllerian derivatives. In the last patient, although AMH serum levels were very low due to a progressive degeneration of testicular tissue, molecular analysis of the AMH gene suggested that end-organ resistance might be the cause of the persistence of müllerian ducts. CONCLUSION: PMDS is not extremely rare. Many diagnostic mistakes are made which could be prevented by performing pelvic or inguinal ultrasonography before surgical treatment of bilateral cryptorchidism or irreducible inguinal hernia. Prognosis depends upon the integrity of the testicular tissue, sometimes compromised for yet unexplained reasons, and upon the successful correction of cryptorchidism, which is complicated by the close anatomical relationship between the vasa deferentia and the Müllerian derivatives.

Adolescent↗