Role of HOXA7 to HOXA13 and PBX1 genes in various forms of MRKH syndrome (congenital absence of uterus and vagina)

The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome refers to the congenital absence or severe hypoplasia of the female genital tract, often described as uterovaginal aplasia which is the prime feature of the syndrome. It is the second cause of primary amenorrhea after gonadal dysgenesis and occurs in ~1 in 4500 women. Aetiology of this syndrome remains poorly understood. Frequent association of other malformations with the MRKH syndrome, involving kidneys, skeleton and ears, suggests the involvement of major developmental genes such as those of the HOX family. Indeed mammalian HOX genes are well known for their crucial role during embryogenesis, particularly in axial skeleton, hindbrain and limb development. More recently, their involvement in organogenesis has been demonstrated notably during urogenital differentiation. Although null mutations of HOX genes in animal models do not lead to MRKH-like phenotypes, dominant mutations in their coding sequences or aberrant expression due to mutated regulatory regions could well account for it. Sequence analysis of coding regions of HOX candidate genes and of PBX1, a likely HOX cofactor during Müllerian duct differentiation and kidney morphogenesis, did not reveal any mutation in patients showing various forms of MRKH syndrome. This tends to show that HOX genes are not involved in MRKH syndrome. However it does not exclude that other mechanisms leading to HOX dysfunction may account for the syndrome

Malnutrition and Mortality Patterns among Internally Displaced and Non-Displaced Population Living in a Camp, a Village or a Town in Eastern Chad

BACKGROUND: Certain population groups have been rendered vulnerable in Chad because of displacement of more than 200,000 people over the last three years as a result of mass violence against civilians in the east of the country. The objective of the study was to assess mortality and nutritional patterns among displaced and non-displaced population living in camps, villages and a town in the Ouddaï and Salamat regions of Chad. METHODOLOGY: Between May and October 2007, two stage, 30-cluster household surveys were conducted among 43,900 internally displaced persons (IDPs) living in camps in Ouaddai region (n = 898 households), among 19,400 non-displaced persons (NDPs) living in 42 villages in Ouaddai region (n = 900 households) and among 17,000 NDPs living in a small town in Salamat region (n = 901 households). Data collection included anthropometric measurements, measles vaccination rates and retrospective mortality. Crude mortality rate (CMR), mortality rate among children younger than 5 years (U5MR), causes of death and the prevalence of wasting (weight-for-height z score <-2) among children aged 6 to 59 months were the main outcome measures. CONCLUSIONS: The CMR among the 4902 IDPs in Gozbeida camps, 4477 NDPs living in a village and 4073 NDPs living in a town surveyed was 1.8 (95% CI, 1.2-2.8), 0.3 (95% CI, 0.2-0.4), 0.3 (95% CI, 0.2-0.5) per 10,000 per day, respectively. The U5MR in a camp (n = 904), a village (n = 956) and a town (n = 901) was 4.1 (95% CI, 2.1-7.7), 0.5 (95% CI, 0.3-0.9) and 0.7 (95% CI, 0.4-1.4) per 10,000 per day, respectively. Diarrhoea was reported to be the main cause of death. Acute malnutrition rates (according to the WHO definition) among 904 IDP children, 956 NDPs children living in a village, 901 NDP children living in a town aged 6 to 59 months were 20.6% (95% CI, 17.9%-23.3%), 16.4% (95% CI, 14.0%-18.8%) and 10.1% (95% CI, 8.1%-12.2%) respectively. The study found a high mortality rate among IDPs and an elevated prevalence of wasting not only in IDP camps but also in villages located in the same region. The town-dweller population remains at risk of malnutrition. Appropriate contingency plans need to be made to ensure acceptable living standards for these populations

Inducible expression of beta defensins by human respiratory epithelial cells exposed to Aspergillus fumigatus organisms

<p>Abstract</p> <p>Background</p> <p><it>Aspergillus fumigatus</it>, a saprophytic mould, is responsible for life-threatening, invasive pulmonary diseases in immunocompromised hosts. The role of the airway epithelium involves a complex interaction with the inhaled pathogen. Antimicrobial peptides with direct antifungal and chemotactic activities may boost antifungal immune response.</p> <p>Results</p> <p>The inducible expression of defensins by human bronchial epithelial 16HBE cells and A549 pneumocyte cells exposed to <it>A. fumigatus </it>was investigated. Using RT-PCR and real time PCR, we showed an activation of hBD2 and hBD9 defensin genes: the expression was higher in cells exposed to swollen conidia (SC), compared to resting conidia (RC) or hyphal fragments (HF). The kinetics of defensin expression was different for each one, evoking a putative distinct function for each investigated defensin. The decrease of defensin expression in the presence of heat-inactivated serum indicated a possible link between defensins and the proteins of the host complement system. The presence of defensin peptide hBD2 was revealed using immunofluorescence that showed a punctual cytoplasmic and perinuclear staining. Quantification of the cells stained with anti hBD2 antibody demonstrated that SC induced a greater number of cells that synthesized hBD2, compared to RC or HF. Labelling of the cells with anti-hBD-2 antibody showed a positive immunofluorescence signal around RC or SC in contrast to HF. This suggests co-localisation of hBD2 and digested conidia. The HBD2 level was highest in the supernatants of cells exposed to SC, as was determined by sandwich ELISA. Experiments using neutralising anti-interleukine-1β antibody reflect the autocrine mechanism of defensin expression induced by SC. Investigation of defensin expression at transcriptional and post-transcriptional levels demonstrated the requirement of transcription as well as new protein synthesis during <it>A. fumigatus </it>defensin induction. Finally, induced defensin expression in primary culture of human respiratory cells exposed to <it>A. fumigatus </it>points to the biological significance of described phenomena.</p> <p>Conclusion</p> <p>Our findings provide evidence that respiratory epithelium might play an important role in the immune response during <it>Aspergillus </it>infection. Understanding the mechanisms of regulation of defensin expression may thus lead to new approaches that could enhance expression of antimicrobial peptides for potential therapeutic use during aspergillosis treatment.</p

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

The Mayer-Rokitansky-Küster-Hauser syndrome (congenital absence of uterus and vagina) – phenotypic manifestations and genetic approaches

The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome affects at least 1 out of 4500 women and has for a long time been considered as a sporadic anomaly. Congenital absence of upper vagina and uterus is the prime feature of the disease which, in addition, is often found associated with unilateral renal agenesis or adysplasia as well as skeletal malformations (MURCS association). The phenotypic manifestations of MRKH overlap various other syndromes or associations and thus require accurate delineation. Since MRKH manifests itself in males, the term GRES syndrome (Genital, Renal, Ear, Skeletal) might be more appropriate when applied to both sexes. The MRKH syndrome, when described in familial aggregates, seems to be transmitted as an autosomal dominant trait with an incomplete degree of penetrance and variable expressivity. This suggests the involvement of either mutations in a major developmental gene or a limited chromosomal deletion. Until recently progress in understanding the genetics of MRKH syndrome has been slow, however, now HOX genes have been shown to play key roles in body patterning and organogenesis, and in particular during genital tract development. Expression and/or function defects of one or several HOX genes may account for this syndrome

Culture, Neurobiology, and Human Behavior: New Perspectives in Anthropology

Our primary goal in this article is to discuss the cross-talk between biological and cultural factors that become manifested in the individual brain development, neural wiring, neurochemical homeostasis, and behavior. We will show that behavioral propensities are the product of both cultural and biological factors and an understanding of these interactive processes can provide deep insights into why people behave the way they do. This interdisciplinary perspective is offered in an effort to generate dialog and empirical work among scholars interested in merging aspects of anthropology and neuroscience, and anticipates that biological and cultural anthropology converge. We discuss new theoretical developments, hypothesis-testing strategies, and cross-disciplinary methods of observation and data collection. We believe that the exigency of integrating anthropology and the neurosciences is indisputable and anthropology's role in an emerging interdisciplinary science of human behavior will be critical because its focus is, and has always been, on human biological and cultural systems

Partial SHOX duplications associated with various cases of congenital uterovaginal aplasia (MRKH syndrome): A tangible evidence but a puzzling mechanism

The Mayer-Rokitansky-K&uuml;ster-Hauser (MRKH) syndrome is the most severe form of congenital malformation of the inner female reproductive tract. It is diagnosed as such when the uterus, the upper vagina and optionally the Fallopian tubes are absent. It accounts for approximately 1 in 5000 live-born females and has been classified in two subtypes: type 1 in the presence of isolated uterovaginal aplasia and type 2 when associated in various combinations with extragenital malformations of the kidneys, skeleton, heart and auditory system. Most cases of MRKH syndrome are sporadic, although a significant number of many familial cases have been reported to date. Despite numerous studies, the genetics of the syndrome remains largely unknown and appears to be heterogeneous: chromosomal abnormalities and some candidate gene variants appear to be associated with a few cases; others have been suggested but not yet confirmed. To date, mainly the GREB1L gene appears to be a serious candidate. Among the remaining hypotheses, the controversial contribution of partial duplications of the SHOX gene is still puzzling, as the deficiency of this gene is a major cause of skeletal adysplasia syndromes. We have attempted to resolve this controversy in a study of 60 MRKH cases. Our results tend to show that SHOX duplications can be the origin of a genetic mechanism responsible for MRKH syndrome

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

Letter to the Editor concerning the high incidence of MRKH syndrome in third-generation DES women

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