Rapid Trio Exome Sequencing for Autosomal Recessive Renal Tubular Dysgenesis in Recurrent Oligohydramnios.
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ABSTRACT:
SUBMITTER: Lin SY
PROVIDER: S-EPMC8255961 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Introduction:Autosomal recessive renal tubular dysgenesis (ARRTD) caused by inactivation mutations in AGT, REN, ACE, and AGTR is a very rare but fatal disorder with an unknown prevalence. Methods:We report 6 Taiwanese individuals with ARRTD from 6 unrelated families diagnosed by renal histology. Clinical features, outcome, and prevalence of carrier heterozygosity were examined. Results:All patients exhibited antenatal oligohydramnios, postnatal anuria, pulmonary hypoplasia, and profound hypotension refractory to interventions. Angiotensinogen (AGT) protein levels were diminished in the liver, along with reduced serum AGT, angiotensin I (Ang I) and angiotensin II (Ang II) levels. Neonatal demise occurred in all but 1 case. All individuals carried the same homozygous E3_E4 del:2870bp deletion+9bp insertion in AGT, which led to a truncated protein (1-292 amino acid). The allelic frequency of this heterozygous AGT mutation was approximately 1.2% (6/500), suggesting that ARRTD may not be exceedingly rare in Taiwan. This mutation results in skipping of exons encoding the serpin domain of AGT, which is important for renin interaction and the generation of truncated protein. In silico modeling revealed a diminished interaction between mutant AGT and renin. One patient survived after responding to high-dose hydrocortisone therapy, with resolution of profound hypotension, accompanied by an increase in serum AGT, Ang I, and Ang II levels. Conclusion:This AGT mutation may lead to the diminished interaction with renin and decreased Ang I and Ang II generation. Hydrocortisone may potentially rescue cases of ARRTD caused by this truncated AGT.
| S-EPMC7609895 | biostudies-literature
Project description:We has identified a founder homozygous E3_E4 del: 2870 bp deletion + 9 bp insertion in AGT gene encoding angiotensinogen responsible for autosomal recessive renal tubular dysgenesis (ARRTD) with nearly-fatal outcome. High-dose hydrocortisone therapy successfully rescued one patient with an increased serum Angiotensinogen (AGT), Ang I, and Ang II levels. The pathogenesis of ARRTD caused by this AGT mutation and the potential therapeutic effect of hydrocortisone were examined by in vitro functional studies. The expression of this truncated AGT protein was relatively low with a dose-dependent manner. This truncated mutation diminished the interaction between mutant AGT and renin. The truncated AGT also altered the glucocorticoid receptor (GR)-dependent transactivation, indicating that AGT may affect the development of proximal convoluted tubule by alteration of glucocorticoid-dependent transactivation. In hepatocytes, hydrocortisone increased the AGT level by accentuating the stability of mutant AGT and increasing its binding with renin. Therefore, hydrocortisone may exert the therapeutic effect through the enhanced stability and interaction with renin of truncated AGT in patients carrying this AGT mutation.
| S-EPMC8065467 | biostudies-literature
Project description:Autosomal Recessive Renal Tubular Dysgenesis (AR-RTD) is a fatal genetic disorder characterized by complete absence or severe depletion of proximal tubules (PT) in patients harboring pathogenic variants in genes involved in the Renin-Angiotensin-Aldosterone System. To uncover the pathomechanism of AR-RTD, differentiation of ACE-/- and AGTR1-/- induced pluripotent stem cells (iPSCs) and AR-RTD patient-derived iPSCs into kidney organoids is leveraged. Comprehensive marker analyses show that both mutant and control organoids generate indistinguishable PT in vitro under normoxic (21% O2) or hypoxic (2% O2) conditions. Fully differentiated (d24) AGTR1-/- and control organoids transplanted under the kidney capsule of immunodeficient mice engraft and mature well, as do renal vesicle stage (d14) control organoids. By contrast, d14 AGTR1-/- organoids fail to engraft due to insufficient pro-angiogenic VEGF-A expression. Notably, growth under hypoxic conditions induces VEGF-A expression and rescues engraftment of AGTR1-/- organoids at d14, as does ectopic expression of VEGF-A. We propose that PT dysgenesis in AR-RTD is primarily a non-autonomous consequence of delayed angiogenesis, starving PT at a critical time in their development.
| S-EPMC10710424 | biostudies-literature
Project description:Renal tubular dysgenesis (RTD) is a rare fatal disorder in which there is poor development of proximal tubules, leading to oligohydramnios and the Potter sequences. RTD occurs secondary to renin-angiotensin system (RAS) blockade during the early stages of fetal development or due to autosomal recessive mutation of genes in the RAS pathway. A boy born at 33+1 weeks due to cord prolapse was found to be anuric and hypotensive. Pregnancy was complicated by severe oligohydramnios from gestational age 28+4 weeks. Abdominal sonography revealed diffuse globular enlargement of both kidneys with increased cortical parenchymal echogenicity. Infantogram showed a narrow thoracic cage and skull X-ray showed large fontanelles and wide sutures suggestive of ossification delay. Basal plasma renin activity was markedly elevated and angiotensin-converting enzyme was undetectable. Despite adequate use of medications, peritoneal dialysis, and respiratory support, he did not recover and expired on the 23rd day of life. At first, autosomal recessive polycystic kidney disease was suspected, but severe oligohydramnios along with refractory hypotension, anuria, skull ossification delay and high renin levels made RTD suspicious. ACE gene analysis revealed compound heterozygous pathogenic variations of c.1454.dupC in exon 9 and c.2141dupA in exon 14, confirming RTD. Based on our findings, we propose that, although rare, RTD should be suspected in patients with severe oligohydramnios and refractory hypotension.
| S-EPMC7431287 | biostudies-literature
Project description:Autosomal recessive renal tubular dysgenesis (ARRTD) is a rare and lethal disorder that causes stillbirth or early neonatal death. Most of the reported cases are diagnosed postnatally by a histopathological hallmark of the absence or paucity of differentiated proximal tubules in kidneys. Prenatal diagnosis of ARRTD is challenging because only a few fetal features (e.g., oligohydramnios/anhydramnios, anuria) are associated with this condition. In this study, we report a fetus with ARRTD, which showed anhydramnios and invisible urinary bladder since the second trimester, followed by growth restriction and reversed end diastolic flow in the middle cerebral artery (MCA-REDF). No morphological anomaly was detected on the fetal kidneys during an ultrasound scan. The baby died of refractory hypotension the day after their birth. Genetic analysis of genes that are involved in the renin-angiotensin-aldosterone system (RAAS), which are the known genetic causes of ARRTD, identified a novel, biparental-origin homozygous c.857-619_1269+243delinsTTGCCTTGC mutation in the AGT gene. The mutation is considered as pathogenic because it is cosegregated with ARRTD and detected in other unrelated ARRTD families. Our findings link the fetal ultrasound manifestations to the ARRTD, highlighting clues that are useful for prenatal diagnosis, which warrants confirmatory genotyping of the RAAS genes including oligohydramnios/anhydramnios, anuria (absent filling of a fetal urinary bladder), MCA-REDF, and a morphologically normal kidney.
| S-EPMC6963964 | biostudies-literature
Project description:BackgroundAutosomal-recessive renal tubular dysgenesis (AR-RTD) is a rare genetic disorder caused by defects in the renin-angiotensin system that manifests as fetal anuria leading to oligohydramnios and Potter sequence. Although the most common outcome is neonatal death from renal failure, pulmonary hypoplasia, and/or refractory arterial hypotension; several cases have been reported that describe survival past the neonatal period.MethodsHerein, we report the first family with biallelic ACE variants and more than one affected child surviving past the neonatal period, as well as provide a review of the previously reported 18 cases with better outcomes.ResultsWhile both siblings with identical compound heterozygous ACE variants have received different treatments, neither required renal replacement therapy. We show that both vasopressin and fludrocortisone in the neonatal period may provide survival advantages, though outcomes may also be dependent on the type of gene variant, as well as other factors.ConclusionWhile AR-RTD is most often a lethal disease in the neonatal period, it is not universally so. A better understanding of the factors affecting survival will help to guide prognostication and medical decision-making.
| S-EPMC9034669 | biostudies-literature
Project description:Protein conformational disorders are associated with the appearance, persistence, accumulation, and misprocessing of aberrant proteins in the cell. The etiology of renal tubular dysgenesis (RTD) is linked to mutations in the angiotensin-converting enzyme (ACE). Here, we report the identification of a novel ACE mutation (Q1069R) in an RTD patient. ACE Q1069R is found sequestered in the endoplasmic reticulum and is also subject to increased proteasomal degradation, preventing its transport to the cell surface and extracellular fluids. Modulation of cellular proteostasis by temperature shift causes an extension in the processing time and trafficking of ACE Q1069R resulting in partial rescue of the protein processing defect and an increase in plasma membrane levels. In addition, we found that temperature shifting causes the ACE Q1069R protein to be secreted in an active state, suggesting that the mutation does not affect the enzyme's catalytic properties.
| S-EPMC3111453 | biostudies-literature
Project description:Autosomal recessive polycystic kidney disease is a truly catastrophic monogenetic disease, causing death and end stage renal disease in neonates and children. Using PCK female rats, an orthologous model of autosomal recessive polycystic kidney disease harboring mutant Pkhd1, we tested the hypothesis that intravenous renal cell transplantation with normal Sprague Dawley male kidney cells would improve the polycystic kidney disease phenotype. Cytotherapy with renal cells expressing wild type Pkhd1 and tubulogenic serum amyloid A1 had powerful and sustained beneficial effects on renal function and structure in the polycystic kidney disease model. Donor cell engraftment and both mutant and wild type Pkhd1 were found in treated but not control PCK kidneys 15 weeks after the final cell infusion. To examine the mechanisms of global protection with a small number of transplanted cells, we tested the hypothesis that exosomes derived from normal Sprague Dawley cells can limit the cystic phenotype of PCK recipient cells. We found that renal exosomes originating from normal Sprague Dawley cells carried and transferred wild type Pkhd1 mRNA to PCK cells in vivo and in vitro and restricted cyst formation by cultured PCK cells. The results indicate that transplantation with renal cells containing wild type Pkhd1 improves renal structure and function in autosomal recessive polycystic kidney disease and may provide an intra-renal supply of normal Pkhd1 mRNA.
| S-EPMC4489886 | biostudies-literature
Project description:Mutations of SLC4A1 (AE1) encoding the kidney anion (Cl(-)/HCO(3) (-)) exchanger 1 (kAE1 or band 3) can result in either autosomal dominant (AD) or autosomal recessive (AR) distal renal tubular acidosis (dRTA). The molecular mechanisms associated with SLC4A1 mutations resulting in these different modes of inheritance are now being unveiled using transfected cell systems. The dominant mutants kAE1 R589H, R901X and S613F, which have normal or insignificant changes in anion transport function, exhibit intracellular retention with endoplasmic reticulum (ER) localization in cultured non-polarized and polarized cells, while the dominant mutants kAE1 R901X and G609R are mis-targeted to apical membrane in addition to the basolateral membrane in cultured polarized cells. A dominant-negative effect is likely responsible for the dominant disease because heterodimers of kAE1 mutants and the wild-type protein are intracellularly retained. The recessive mutants kAE1 G701D and S773P however exhibit distinct trafficking defects. The kAE1 G701D mutant is retained in the Golgi apparatus, while the misfolded kAE1 S773P, which is impaired in ER exit and is degraded by proteosome, can only partially be delivered to the basolateral membrane of the polarized cells. In contrast to the dominant mutant kAE1, heterodimers of the recessive mutant kAE1 and wild-type kAE1 are able to traffic to the plasma membrane. The wild-type kAE1 thus exhibits a 'dominant-positive effect' relative to the recessive mutant kAE1 because it can rescue the mutant proteins from intracellular retention to be expressed at the cell surface. Consequently, homozygous or compound heterozygous recessive mutations are required for presentation of the disease phenotype. Future work using animal models of dRTA will provide additional insight into the pathophysiology of this disease.
| S-EPMC2702069 | biostudies-literature
Project description:Distal renal tubular acidosis is a rare renal tubular disorder characterized by hyperchloremic metabolic acidosis and impaired urinary acidification. Mutations in three genes (ATP6V0A4, ATP6V1B1 and SLC4A1) constitute a monogenic causation in 58-70% of familial cases of distal renal tubular acidosis. Recently, mutations in FOXI1 have been identified as an additional cause. Therefore, we hypothesized that further monogenic causes of distal renal tubular acidosis remain to be discovered. Panel sequencing and/or whole exome sequencing was performed in a cohort of 17 families with 19 affected individuals with pediatric onset distal renal tubular acidosis. A causative mutation was detected in one of the three "classical" known distal renal tubular acidosis genes in 10 of 17 families. The seven unsolved families were then subjected to candidate whole exome sequencing analysis. Potential disease causing mutations in three genes were detected: ATP6V1C2, which encodes another kidney specific subunit of the V-type proton ATPase (1 family); WDR72 (2 families), previously implicated in V-ATPase trafficking in cells; and SLC4A2 (1 family), a paralog of the known distal renal tubular acidosis gene SLC4A1. Two of these mutations were assessed for deleteriousness through functional studies. Yeast growth assays for ATP6V1C2 revealed loss-of-function for the patient mutation, strongly supporting ATP6V1C2 as a novel distal renal tubular acidosis gene. Thus, we provided a molecular diagnosis in a known distal renal tubular acidosis gene in 10 of 17 families (59%) with this disease, identified mutations in ATP6V1C2 as a novel human candidate gene, and provided further evidence for phenotypic expansion in WDR72 mutations from amelogenesis imperfecta to distal renal tubular acidosis.
| S-EPMC7039771 | biostudies-literature