Utero-vaginal aplasia (Mayer-Rokitansky-Küster-Hauser syndrome) associated with deletions in known DiGeorge or DiGeorge-like loci

<p>Abstract</p> <p>Background</p> <p>Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by congenital aplasia of the uterus and the upper part of the vagina in women showing normal development of secondary sexual characteristics and a normal 46, XX karyotype. The uterovaginal aplasia is either isolated (type I) or more frequently associated with other malformations (type II or Müllerian Renal Cervico-thoracic Somite (MURCS) association), some of which belong to the malformation spectrum of DiGeorge phenotype (DGS). Its etiology remains poorly understood. Thus the phenotypic manifestations of MRKH and DGS overlap suggesting a possible genetic link. This would potentially have clinical consequences.</p> <p>Methods</p> <p>We searched DiGeorge critical chromosomal regions for chromosomal anomalies in a cohort of 57 subjects with uterovaginal aplasia (55 women and 2 aborted fetuses). For this candidate locus approach, we used a multiplex ligation-dependent probe amplification (MLPA) assay based on a kit designed for investigation of the chromosomal regions known to be involved in DGS.</p> <p>The deletions detected were validated by Duplex PCR/liquid chromatography (DP/LC) and/or array-CGH analysis.</p> <p>Results</p> <p>We found deletions in four probands within the four chromosomal loci 4q34-qter, 8p23.1, 10p14 and 22q11.2 implicated in almost all cases of DGS syndrome.</p> <p>Conclusion</p> <p>Uterovaginal aplasia appears to be an additional feature of the broad spectrum of the DGS phenotype. The DiGeorge critical chromosomal regions may be candidate loci for a subset of MRKH syndrome (MURCS association) individuals. However, the genes mapping at the sites of these deletions involved in uterovaginal anomalies remain to be determined. These findings have consequences for clinical investigations, the care of patients and their relatives, and genetic counseling.</p

Étude génétique du développement normal et pathologique des canaux de Müller

Female genital tract onset and differentiation is a complex developmental process. Molecular and cellular mechanisms involved in this process are triggered by numerous genes and signaling pathways in between which multiple interactions take place. In a clinical point of view, accurate knowledge of these interactions is of great importance, for the understanding of pathogenic mechanisms causing congenital anomalies of the reproductive system in women. Complementarily, genetic studies of malformation syndromes affecting the female inner genital tract, contribute to better define the molecular cascade eliciting the development of this essential organ. In this context two research programs, one fundamental and another clinical, have been developed. In the first one, the role of mTcf7l2 gene was investigated during inner male and female genital tract development in the mouse. This gene encodes a nuclear component of the Wnt pathways and is subject to many alternative splicing events. Its expression pattern was established during the müllerian ducts (the anlagen of inner female genital tract) differentiation. The overall results suggest that mTcf7l2 takes part in the sexually dimorphic development of the inner genital tract. The second part of the program consisted in a genetic study of a cohort of patients presenting with diagnosed MRKH syndrome. This study has led us to define four microdeletions located within four discrete critical regions linked the DiGeorge syndrome, a disease of which the malformation spectrum overlaps with that of MRKH syndrome. This has raised the question whether MRKH and DiGeorge syndromes correspond to various manifestations of a unique and heterogeneous deletion syndrome or are parts of a wider contiguous gene syndrome, according to the affected chromosome. Accurate delineation of one of these deletions has led to define ITIH5 as a candidate gene. Preliminary expression studies in the mouse suggest that this gene would play a major role during müllerian ducts differentiation.La mise en place et la différenciation du tractus génital femelle est un processus développemental complexe. Les mécanismes moléculaires et cellulaires impliqués dans ce processus sont régis par de nombreux gènes et voies de signalisation, entre lesquels les interactions sont multiples. Leur connaissance précise est d'une grande importance d'un point de vue clinique pour la compréhension des mécanismes pathogéniques à l'origine de malformations congénitales. Inversement, l'étude génétique des syndromes malformatifs affectant le tractus reproducteur féminin contribue à la définition des cascades génétiques régulant la mise en place de cet organe essentiel. Dans ce cadre, deux axes de recherche, l'un fondamental, l'autre clinique, ont été suivis dans cette étude. Dans la première approche, le rôle du gène mTcf7l2 a été étudié au cours du développement des voies génitales internes mâle et femelle chez la souris. Ce gène, codant pour un co-facteur transcriptionnel de la voie de signalisation Wnt, est soumis à de nombreux événements d'épissage alternatif menant à la synthèse de plusieurs isoformes protéiques. La caractérisation de son expression dans les canaux de Müller (ébauches embryonnaires des voies génitales internes femelles) en cours de différenciation indique qu'il pourrait être impliqué dans la régulation transcriptionnelle de gènes cibles lors de ce processus. L'ensemble des résultats obtenus au cours de cette étude suggère que les produits du gène mTcf7l2 participent au développement sexuellement dimorphique du tractus génital interne. La seconde partie concerne une étude génétique menée sur une cohorte de patientes atteintes du syndrome d'aplasie utéro-vaginale congénitale, dit syndrome de Mayer-Rokitansky-Küster-Hauser (MRKH). Cette étude nous a conduits à caractériser, chez quatre patientes non apparentées, quatre microdélétions au sein des régions critiques du syndrome de DiGeorge, une pathologie malformative congénitale dont le spectre de malformations chevauche celui du syndrome MRKH. La question d'une seule et même entité clinique aux manifestations phénotypiques très variables, ou d'un syndrome dit de gènes contigus selon les cas, peut se poser. La délimitation précise de l'une de ces microdélétions a abouti à la définition d'un gène candidat, ITIH5, dont les études préliminaires de profil d'expression chez la souris suggèrent qu'il joue un rôle très important lors du processus de différenciation des canaux müllériens

Sororin pre-mRNA splicing is required for proper sister chromatid cohesion in human cells.

International audienceSister chromatid cohesion, which depends on cohesin, is essential for the faithful segregation of replicated chromosomes. Here, we report that splicing complex Prp19 is essential for cohesion in both G2 and mitosis, and consequently for the proper progression of the cell through mitosis. Inactivation of splicing factors SF3a120 and U2AF65 induces similar cohesion defects to Prp19 complex inactivation. Our data indicate that these splicing factors are all required for the accumulation of cohesion factor Sororin, by facilitating the proper splicing of its pre-mRNA. Finally, we show that ectopic expression of Sororin corrects defective cohesion caused by Prp19 complex inactivation. We propose that the Prp19 complex and the splicing machinery contribute to the establishment of cohesion by promoting Sororin accumulation during S phase, and are, therefore, essential to the maintenance of genome stability

Étude génétique du développement normal et pathologique des canaux de Müller

De nombreux gènes et voies de signalisation régissent le développement du tractus génital femelle. Leur connaissance précise est d une grande importance d un point de vue clinique pour la compréhension des mécanismes pathogéniques à l origine de malformations congénitales. Dans ce cadre, deux axes de recherche, fondamental et clinique, ont été suivis. En premier lieu, le rôle du gène Tcf7l2 a été étudié au cours du développement des voies génitales chez la souris. La caractérisation de son expression dans les canaux de Müller suggère qu il participe à leur différenciation par la régulation de gènes cibles. La seconde partie est une étude génétique menée sur des patientes atteintes du syndrome d aplasie utéro-vaginale congénitale (syndrome de Mayer-Rokitansky-Küster-Hauser). 4 délétions distinctes ont été identifiées chez 4 patientes. L une d elles nous a conduits à caractériser ITIH5 comme gène candidat, l étude de son expression chez la souris corroborant cette hypothèse.Numerous genes and signaling pathways trigger female genital tract development. Accurate knowledge of their interactions is of great importance for the understanding of pathogenic mechanisms causing congenital anomalies of this organ. In this context, two research programs, fundamental and clinical, have been developed. In the first one, the role of Tcf7l2 gene was investigated during inner genital tract development in the mouse. Characterization of its expression in the müllerian ducts suggests that it takes part in their differentiation through regulation of target genes. The second part consisted in a genetic study of patients presenting with congenital aplasia of uterus and vagina (Mayer-Rokitansky-Küster-Hauser syndrome). 4 deletions have been found in 4 patients. Accurate delineation of one of these deletions has led to define ITIH5 as a candidate gene. Expression studies in the mouse suggest that this gene would play a major role during müllerian ducts differentiation.RENNES1-BU Sciences Philo (352382102) / SudocSudocFranceF

Protein expression is increased by a class III AU-rich element and tethered CUG-BP1.

International audienceIn mammalian somatic cells, the post-transcriptional control of cytokine or proto-oncogene expression is often achieved by factors binding to sequence elements in the 3' untranslated region (3'UTR). The most studied are the AU-rich elements (ARE) that have been divided into three classes. Here, we show that in mammalian cells, the presence of the class III c-jun ARE in the 3'UTR of a reporter mRNA enhanced reporter protein expression. In contrast, the presence of a class II ARE in the 3'UTR decreased reporter protein expression. CUG-BP1/CELF1 is able to bind c-jun ARE. Protein expression was enhanced similarly to what was observed for c-jun ARE when the reporter mRNA contained a synthetic CUG-BP1/CELF1-binding site, or when this protein was tethered to the 3'UTR of a reporter mRNA. These results reveal an unexpected complexity of ARE-mediated post-transcriptional regulations, and indicate a function for CUG-BP1/CELF1 in class III ARE directed regulations

Le syndrome de Mayer-Rokitansky-Küster-Hauser (MRKH) : clinique et génétique [The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome: clinical description and genetics]

International audienceThe Mayer-Rokitansky-K?r-Hauser (MRKH) syndrome is characterized by congenital aplasia of the uterus and the upper part (two-third) of the vagina. It may be isolated (type I) or associated with other malformations (type II or MURCS association). These latter involve the upper urinary tract, the skeleton and, to a lesser extent, the otologic sphere or the heart. The incidence of MRKH syndrome has been estimated as 1 in 4500 women. The prime feature is a primary amenorrhea in women presenting otherwise with normal development of secondary sexual characteristics and normal external genitalia. However, the vagina is reduced to a vaginal dimple with variable depth. The ovaries are normal and functional as well as the endocrine status. Karyotype is 46,XX, with no visible chromosome modification. The phenotypic manifestations of MRKH syndrome overlap with various other syndromes or malformations and thus require accurate delineation as well as differential diagnosis. For a long time, the syndrome has been considered as a sporadic anomaly, but increasing familial cases now support the hypothesis of a genetic cause currently under investigation. The syndrome appears to be transmitted as an autosomal dominant trait with incomplete penetrance and variable expressivity

The developing female genital tract: from genetics to epigenetics.

International audienceThe mammalian female reproductive tract develops from the Mullerian ducts which differentiate, in a cranial to caudal direction, into oviducts, uterine horns, cervix and the anterior vagina. The developmental processes taking place during this organogenesis are notably under the control of steroid hormones, such as members of the Wnt and Hox families, which regulate key developmental genes. At later stages, steroid hormones also participate in the development of the female genital tract. Chemical compounds homologous to steroids can thus act as agonists or antagonists in fetuses exposed to them. These so-called endocrine disruptors are nowadays found in increasing amounts in the environment and may therefore have a particular impact on such developing organs. Epidemiological studies have revealed that endocrine disruptors have had drastic effects on female health and fertility during the last decades. Furthermore, these adverse effects might be transmitted to subsequent generations through epigenetic modifications. Given the potential hazard of inherited epigenetic marks altering reproduction and/or human health, such molecular mechanisms must be urgently investigated. This review aims to summarize the cellular and molecular mechanisms involved in female genital tract development, to highlight key genes involved in this process and to present epigenetic mechanisms triggered by endocrine disruptors and their consequences in regard to female reproductive tract development

Original Article PBX1 intracellular localization is independent of MEIS1 in epithelial cells of the developing female genital tract

ABSTRACT While studies have highlighted the role of HOXA9-13 and PBX1 homeobox genes during the development of the female genital tract, the molecular mechanisms triggered by these genes are incompletely elucidated. In several developmental pathways, PBX1 binds to MEINOX family members in the cytoplasm to be imported into the nucleus where they associate with HOX proteins to form a higher complex that modulates gene expression. This concept has been challenged by a recent report showing that in some cell cultures, PBX1 nuclear localization might be regulated independently of MEINOX proteins (Kilstrup-Nielsen et al., 2003). Our work gives the first illustration of this alternative mechanism in an organogenesis process. Indeed, we show that PBX1 is mostly cytoplasmic in epithelial endometrial cells of the developing female genital tract despite the nuclear localization of MEIS1. We thus provide evidence for a control of PBX1 intracellular distribution which is independent of MEINOX proteins, but is cell cycle correlated

Involvement of ITIH5, a candidate gene for congenital uterovaginal aplasia (Mayer-Rokitansky-Küster-Hauser syndrome), in female genital tract development.

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