Inherited renal tubular dysgenesis: the first patients surviving the neonatal period

Renal tubular dysgenesis (RTD) is a clinical disorder either acquired during fetal development or inherited as an autosomal recessive condition. Inherited RTD is caused by mutations in the genes encoding the components of the renin-angiotensin system angiotensinogen, renin, angiotensin-converting enzyme and angiotensin II receptor type 1. Inherited RTD is characterized by early onset oligohydramnios, skull ossification defects, preterm birth and neonatal pulmonary and renal failure. The histological hallmark is the absence or poor development of proximal tubules. So far, all patients died either in utero or shortly after birth. We report the first patients with inherited RTD surviving the neonatal period and still being alive. Genetic and functional analysis of the renin-angiotensin system contributes to the diagnosis of RTD. In conclusion, the clinical diagnosis of inherited RTD is easily missed after birth without renal biopsy or information on affected family members. Genetic and functional analysis of the renin-angiotensin system contributes to correct diagnosi

Interaction between galectin-3 and cystinosin uncovers a pathogenic role of inflammation in kidney involvement of cystinosis.

Inflammation is involved in the pathogenesis of many disorders. However, the underlying mechanisms are often unknown. Here, we test whether cystinosin, the protein involved in cystinosis, is a critical regulator of galectin-3, a member of the β-galactosidase binding protein family, during inflammation. Cystinosis is a lysosomal storage disorder and, despite ubiquitous expression of cystinosin, the kidney is the primary organ impacted by the disease. Cystinosin was found to enhance lysosomal localization and degradation of galectin-3. In Ctns-/- mice, a mouse model of cystinosis, galectin-3 is overexpressed in the kidney. The absence of galectin-3 in cystinotic mice ameliorates pathologic renal function and structure and decreases macrophage/monocyte infiltration in the kidney of the Ctns-/-Gal3-/- mice compared to Ctns-/- mice. These data strongly suggest that galectin-3 mediates inflammation involved in kidney disease progression in cystinosis. Furthermore, galectin-3 was found to interact with the pro-inflammatory cytokine Monocyte Chemoattractant Protein-1, which stimulates the recruitment of monocytes/macrophages, and proved to be significantly increased in the serum of Ctns-/- mice and also patients with cystinosis. Thus, our findings highlight a new role for cystinosin and galectin-3 interaction in inflammation and provide an additional mechanistic explanation for the kidney disease of cystinosis. This may lead to the identification of new drug targets to delay cystinosis progression

Caroli disease, bilateral diffuse cystic renal dysplasia, situs inversus, postaxial polydactyly, and preauricular fistulas: a ciliopathy caused by a homozygous NPHP3 mutation

We report the rare association of Caroli disease (intrahepatic bile duct ectasia associated with congenital hepatic fibrosis), bilateral cystic renal dysplasia, situs inversus, postaxial polydactyly, and preauricular fistulas in a female child. She presented with end-stage renal disease at the age of 1month, followed by a rapidly progressing hepatic fibrosis and dilatation of the intrahepatic bile ducts, leading to secondary biliary cirrhosis and portal hypertension. Combined liver-kidney transplantation was performed at the age of 4years, with excellent outcome. DNA analysis showed a NPHP3 (coding nephrocystin-3) homozygote mutation, confirming that this malformation complex is a ciliopathy. Conclusion: This rare association required an exceptional therapeutic approach: combined simultaneous orthotopic liver and kidney transplantation in a situs inversus recipient. The long-term follow-up was excellent with a very good evolution of the renal and hepatic grafts and normalization of growth and weight. This malformation complex has an autosomal recessive inheritance with a 25% recurrence risk in each pregnanc

Angiotensin I-Converting Enzyme Gln1069Arg Mutation Impairs Trafficking to the Cell Surface Resulting in Selective Denaturation of the C-Domain

Angiotensin-converting enzyme (ACE; Kininase II; CD143) hydrolyzes small peptides such as angiotensin I, bradykinin, substance P, LH-RH and several others and thus plays a key role in blood pressure regulation and vascular remodeling. Complete absence of ACE in humans leads to renal tubular dysgenesis (RTD), a severe disorder of renal tubule development characterized by persistent fetal anuria and perinatal death.Patient with RTD in Lisbon, Portugal, maintained by peritoneal dialysis since birth, was found to have a homozygous substitution of Arg for Glu at position 1069 in the C-terminal domain of ACE (Q1069R) resulting in absence of plasma ACE activity; both parents and a brother who are heterozygous carriers of this mutation had exactly half-normal plasma ACE activity compared to healthy individuals. We hypothesized that the Q1069R substitution impaired ACE trafficking to the cell surface and led to accumulation of catalytically inactive ACE in the cell cytoplasm. CHO cells expressing wild-type (WT) vs. Q1069R-ACE demonstrated the mutant accumulates intracellularly and also that it is significantly degraded by intracellular proteases. Q1069R-ACE retained catalytic and immunological characteristics of WT-ACE N domain whereas it had 10–20% of the nativity of the WT-ACE C domain. A combination of chemical (sodium butyrate) or pharmacological (ACE inhibitor) chaperones with proteasome inhibitors (MG 132 or bortezomib) significantly restored trafficking of Q1069R-ACE to the cell surface and increased ACE activity in the cell culture media 4-fold.Homozygous Q1069R substitution results in an ACE trafficking and processing defect which can be rescued, at least in cell culture, by a combination of chaperones and proteasome inhibitors. Further studies are required to determine whether similar treatment of individuals with this ACE mutation would provide therapeutic benefits such as concentration of primary urine

Mutational analysis of the PLCE1 gene in steroid-resistant nephrotic syndrome

International audienceBackground: Mutations in the PLCE1 gene encoding phospholipase C epsilon 1 (PLCε1) have been recently described in patients with early-onset nephrotic syndrome (NS) and diffuse mesangial sclerosis (DMS). In addition, two cases of PLCE1 mutations associated with focal segmental glomerulosclerosis (FSGS) and later NS onset have been reported. Methods: In order to better assess the spectrum of phenotypes associated with PLCE1 mutations, we performed mutational analysis in a worldwide cohort of 139 patients (95 familial cases belonging to 68 families and 44 sporadic cases) with steroid-resistant NS presenting at a median age of 23.0 months (range 0-373). Results: We identified homozygous or compound heterozygous mutations in 33% (8/24) of DMS cases. PLCE1 mutations were found in 8% (6/78) of FSGS cases without NPHS2 mutations. Nine were novel mutations. No clear genotype-phenotype correlation was observed, with either truncating or missense mutations detected in both DMS and FSGS, and leading to a similar renal evolution. Surprisingly, 3 unaffected and unrelated individuals were also found to carry the homozygous mutations identified in their respective families. Conclusion: PLCE1 is a major gene of DMS and is mutated in a non-negligible proportion of FSGS cases without NPHS2 mutations. Although we did not identify additional variants in 19 candidate genes (16 other PLC genes, BRAF, IQGAP1 and NPHS1), we speculate that other modifier genes or environmental factors may play a role in the renal phenotype variability observed in individuals bearing PLCE1 mutations. This observation needs to be considered in the genetic counselling offered to patients

Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia

Autosomal-dominant tubulo-interstitial kidney disease (ADTKD) encompasses a group of disorders characterized by renal tubular and interstitial abnormalities, leading to slow progressive loss of kidney function requiring dialysis and kidney transplantation. Mutations in UMOD, MUC1, and REN are responsible for many, but not all, cases of ADTKD. We report on two families with ADTKD and congenital anemia accompanied by either intrauterine growth retardation or neutropenia. Ultrasound and kidney biopsy revealed small dysplastic kidneys with cysts and tubular atrophy with secondary glomerular sclerosis, respectively. Exclusion of known ADTKD genes coupled with linkage analysis, whole-exome sequencing, and targeted re-sequencing identified heterozygous missense variants in SEC61A1—c.553A>G (p.Thr185Ala) and c.200T>G (p.Val67Gly)—both affecting functionally important and conserved residues in SEC61. Both transiently expressed SEC6A1A variants are delocalized to the Golgi, a finding confirmed in a renal biopsy from an affected individual. Suppression or CRISPR-mediated deletions of sec61al2 in zebrafish embryos induced convolution defects of the pronephric tubules but not the pronephric ducts, consistent with the tubular atrophy observed in the affected individuals. Human mRNA encoding either of the two pathogenic alleles failed to rescue this phenotype as opposed to a complete rescue by human wild-type mRNA. Taken together, these findings provide a mechanism by which mutations in SEC61A1 lead to an autosomal-dominant syndromic form of progressive chronic kidney disease. We highlight protein translocation defects across the endoplasmic reticulum membrane, the principal role of the SEC61 complex, as a contributory pathogenic mechanism for ADTKD

Tumor suppressor gene WT1 in renal diseases

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Expression des produits des gènes PKD1 et PKD2 au cours de la néphrogènèse chez l' homme et localisations subcellulaires et fonctions de la polycystine

La polykystose rénale autosomique dominante est une des maladies monogéniques les plus fréquentes. Elle est caractérisée par le développement de kystes rénaux bilatéraux, conduisant progressivement à une insuffisance rénale terminale vers la sixième décade. La vaste majorité des cas est due à des mutations du gène PKD1 codant pour une large protéine transmembranaire dénommée polycystine-1. Plus rarement, la maladie est causée par des mutations situées sur le gène PKD2 codant pour la polycystine-2. La fonction précise des polycystines restent encore à établir. Leurs structures primaires suggèrent que la première puisse être un récepteur transmembranaire impliqué dans les interactions cellule-cellule et/ou cellule-matrice extracellulaire, alors que la seconde serait un canal calcique.PARIS5-BU-Necker : Fermée (751152101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF