[Rectourethral fistulae: diagnosis and management. Review of the literature]. / Fistules urétrorectales : quelle prise en charge diagnostique et thérapeutique ? Revue de la littérature et état de l'art.

INTRODUCTION: Rectourethral fistulae are predominantly of iatrogenous origin. They alter the patient's quality of life and are difficult to manage from a medical standpoint. PATIENTS AND METHODS: The major series of patients of the last 20 years have been analyzed, in order to define the best management of rectourethral fistulae. RESULTS: Many surgical techniques have been tried, as well as several protocols, ranging from simple urinary and fecal diversion to diversion followed by reconstruction and regional flap in case of tissue damage. CONCLUSION: The fistula's cause and the use of radiotherapy had a major impact on its prognosis. The best-suited protocol was the 3-step protocol, which has been described within. The flap, which seemed to have the best results, was the gracilis muscle flap.

Functional properties of the R154X HNF-4alpha protein generated by a mutation associated with maturity-onset diabetes of the young, type 1.

Mutations in the hepatocyte nuclear factor 4alpha (HNF-4alpha) gene are associated with one form of maturity-onset diabetes of the young (MODY1). The R154X mutation generates a protein lacking the E-domain which is required for normal HNF-4alpha functions. Since pancreatic beta-cell dysfunction is a feature of MODY1 patients, we compared the functional properties of the R154X mutant in insulin-secreting pancreatic beta-cells and non-beta-cells. The R154X mutation did not affect nuclear localisation in beta-cells and non-beta-cells. However, it did lead to a greater impairment of HNF-4a function in beta-cells compared to non-beta-cells, including a complete loss of transactivation activity and a dominant-negative behaviour. .

Functional study of the E276Q mutant hepatocyte nuclear factor-4alpha found in type 1 maturity-onset diabetes of the young: impaired synergy with chicken ovalbumin upstream promoter transcription factor II on the hepatocyte nuclear factor-1 promoter.

Seven mutations in the hepatocyte nuclear factor (HNF)-4alpha gene have been shown to correlate with type 1 maturity-onset diabetes of the young (MODY 1), a monogenic form of type 2 diabetes. Up to now, only the functional properties of two MODY 1 HNF-4alpha mutants, Q268X and V393I, have been investigated to address how the mutations in the HNF-4alpha gene, found by genetic studies, can give rise to impaired activities of mutated HNF-4alpha proteins and can cause this disease. The E276Q mutation results in a nonconservative substitution occurring in the HNF-4alpha E domain, which is involved in dimerization and transactivation activities as well as in protein-protein interactions with other transcription factors or coactivators. Using the mutated human HNF-4alpha2, we have found that, in the absence of chicken ovalbumin upstream promoter transcription factor II (COUP TFII), the E276Q substitution does not significantly affect the dimerization and transactivating activities of HNF-4alpha, at least on the promoters studied herein. On the other hand, in the presence of COUP TFII, the substitution impairs the enhancement of HNF-4-mediated activation of HNF-1 promoter. The impaired synergy between COUP TFII and HNF-4 on the HNF-1 promoter results from an alteration of their interaction. HNF-1 expression plays a crucial role in transactivation of insulin promoter and of numerous genes coding for enzymes involved in glucose homeostasis. Therefore, its downregulation resulting from the E276Q mutation in HNF-4alpha gene most probably impairs the function of pancreatic beta-cells.

The activity of the activation function 2 of the human hepatocyte nuclear factor 4 (HNF-4alpha) is differently modulated by F domains from various origins.

Hepatocyte nuclear factor 4 (HNF-4) is a member of the nuclear hormone-receptor superfamily, which plays an important role in the regulation of several genes involved in numerous metabolic pathways. HNF-4 contains a DNA-binding domain located in domain C and two activation-function domains, designated AF-1 and AF-2, located in domains A/B and E, respectively. The seven isoforms of human HNF-4, termed alpha1-alpha6 and gamma, differ mainly by their A/B and F domains. The high sequence variability of the F domain led us to investigate whether this domain modulates the transcriptional activity of HNF-4. Using constructs having the same core receptor and different F domains, we observed that the F domains of HNF-4 modulate the transactivating activity of the full-length HNF-4. A more precise analysis using HNF-4alpha AF-2 fused to GAL4 protein and various F domains demonstrated that F domains of isoforms alpha3 and gamma exhibited inhibitory effects on the activation function AF-2 but that their inhibition behaviours were weaker than that of HNF-4alpha2 F domain, which has been reported previously. The presence of domain F results in a decreased interaction with the co-activator glucocorticoid receptor-interacting protein 1. For a given F domain, the modulating effects on the full-length HNF-4 as well as on the AF-2 depended on the target promoters. Our results suggest that the presence of domain F results in conformation changes in HNF-4 AF-2 or in its spatial environment, which probably modify the interaction of the AF-2 activation domain with co-factors and transcription factors bound to cis-elements of the target promoters.

A missense mutation in hepatocyte nuclear factor-4 alpha, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus.

Non-insulin-dependent diabetes mellitus (NIDDM) is a heterogeneous disorder characterized by hyperglycemia resulting from defects in insulin secretion and action. Recent studies have found mutations in the hepatocyte nuclear factor-4 alpha gene (HNF-4alpha) in families with maturity-onset diabetes of the young (MODY), an autosomal dominant form of diabetes characterized by early age at onset and a defect in glucose-stimulated insulin secretion. During the course of our search for susceptibility genes contributing to the more common late-onset NIDDM forms, we observed nominal evidence for linkage between NIDDM and markers in the region of the HNF-4alpha/MODY1 locus in a subset of French families with NIDDM diagnosed before 45 yr of age. Thus, we screened these families for mutations in the HNF-4alpha gene. We found a missense mutation, resulting in a valine-to-isoleucine substitution at codon 393 in a single family. This mutation cosegregated with diabetes and impaired insulin secretion, and was not present in 119 control subjects. Expression studies showed that this conservative substitution is associated with a marked reduction of transactivation activity, a result consistent with this mutation contributing to the insulin secretory defect observed in this family.

mRNA expression of HNF-4 isoforms and of HNF-1alpha/HNF-1beta variants and differentiation of human cell lines that mimic highly specialized phenotypes of intestinal epithelium.

The mRNA expression of HNF-4 isoforms and the ratio of HNF-1alpha/HNF-1beta variants in cell lines representing highly specialized phenotypes of human intestinal epithelium were studied by RT-PCR. A strong rise in expression of HNF-4 isoforms alpha2, alpha4 and gamma correlates with commitment into highly differentiated enterocyte-like phenotype of Caco-2 cells which best mimic enterocytes, whereas only isoform alpha4 expression is high in the less differentiated HT-29 G- cells. These increased expressions are not encountered in the highly differentiated mucous-secreting HT-29 MTX cells. Differentiation into highly specialized enterocyte-like Caco-2 cells and mucous-secreting HT-29 MTX cells is accompanied by a moderate rise in HNF-1 without change in the ratio of its variants. Our data corroborate those of Spath et al. (Mol. Cell. Biol., 1997, 17, 1913) in hepatoma cells and suggest that HNF-4 isoforms alpha2, alpha4 and gamma play a major role in the differentiation of enterocytes.