Modeling hereditary distal renal tubular acidosis using patient-derived iPSCs with WDR72 mutations
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PROVIDER: PRJNA1304931 | ENA |
REPOSITORIES: ENA
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Project description:Distal renal tubular acidosis (dRTA) is a rare genetic disorder characterized by impaired urine acidification. The WDR72 gene has recently been implicated in dRTA, though its precise functional mechanisms remain unclear. In this study, we generated induced pluripotent stem cell (iPSC) from a patient with WDR72 mutations to model the disease. Upon differentiation into renal tubular epithelial cells, the wild-type and mutant cells (variants c.1777A>G and c.2522T>A) were analyzed for RNA expression, protein localization, and H+-ATPase trafficking. The results indicated no significant changes in these parameters, with the mutant protein retaining its role in acid-base homeostasis. Transcriptomic analysis revealed the top 10 differentially expressed genes (DEGs) were predominantly associated with the collagen-containing extracellular matrix, suggesting a potential link between WDR72 function and extracellular matrix composition. These findings highlight the value of iPSC-derived cellular models in advancing personalized research on dRTA.
2025-08-28 | GSE305256 | GEO
Project description:BackgroundHereditary spherocytosis (HS) and hereditary hereditary distal renal tubular acidosis (dRTA) are associated with mutations in the SLC4A1 gene encoding the anion exchanger 1. In this study, some patients with clinical evidence of congenital HS and renal symptoms were investigated.MethodsTwelve patients with congenital HS and renal symptoms were recruited from Ali-Asghar Children’s Hospital (Tehran, Iran). A patient suspected of having dRTA was examined using whole exome sequencing method, followed by Sanger sequencing.ResultsOne patient (HS03) showed severe failure to thrive, short stature, frequent urinary infection, and weakness. A homozygote (rs571376371 for c.2494C>T; p.Arg832Cys) and a heterozygote (rs377051298 for c.466C>T; p.Arg156Trp) missense variant were identified in the SLC4A1 and SPTA1 genes, respectively. The compound heterozygous mutations manifested as idRTA and severe HS in patient HS03.ConclusionOur observations, for the first time, revealed clinical and genetic characteristics of idRTA and severe HS in an Iranian patient HS03.
| S-EPMC8487683 | biostudies-literature
Project description:ObjectiveTo study the clinical features of two families with distal renal tubular acidosis (dRTA) and mutations in the pathogenic gene SLC4A1.MethodsFamily investigation, medical history collection, and measurement of biochemical parameters were performed to analyze the clinical phenotype and genetic characteristics of dRTA. Direct sequencing was used to detect SLC4A1 gene mutations.ResultsThree patients in these two families (two of them were mother and son) were diagnosed with dRTA with typical clinical features, including short stature, metabolic acidosis, alkaline urine, hypokalemia, and nephrocalcinosis. SLC4A1 gene analysis showed that all the three patients had a pathogenic missense mutation R589H (c.1766G>A). The child in family 1 had a de novo mutation of SLC4A1, and the child in family 2 had an SLC4A1 gene mutation inherited from the mother, which met the characteristic of autosomal dominant inheritance.ConclusionsThis study reports the R589H mutation in SLC4A1 gene in families with hereditary dRTA for the first time in China. Clinical physicians should perform gene detection for patients suspected of hereditary dRTA to improve the diagnosis and treatment of this disease.
| S-EPMC7389662 | biostudies-literature
Project description:Autosomal recessive distal renal tubular acidosis is usually a severe disease of childhood, often presenting as failure to thrive in infancy. It is often, but not always, accompanied by sensorineural hearing loss, the clinical severity and age of onset of which may be different from the other clinical features. Mutations in either ATP6V1B1 or ATP6V0A4 are the chief causes of primary distal renal tubular acidosis with or without hearing loss, although the loss is often milder in the latter. We describe a kindred with compound heterozygous alterations in ATP6V0A4, where hearing loss was formally diagnosed late in both siblings such that they missed early opportunities for hearing support. This kindred highlights the importance of routine audiologic assessments of all children with distal renal tubular acidosis, irrespective either of age at diagnosis or of which gene is mutated. In addition, when diagnostic genetic testing is undertaken, both genes should be screened irrespective of current hearing status. A strategy for this is outlined.
| S-EPMC3658229 | biostudies-literature
Project description:Renal tubular acidosis (RTA) comprises a group of disorders in which excretion of hydrogen ions or reabsorption of filtered HCO3 is impaired, leading to chronic metabolic acidosis with normal anion gap. In the current review, the focus is placed on the most common type of RTA, Type 1 RTA or Distal RTA (dRTA), which is a rare chronic genetic disorder characterized by an inability of the distal nephron to secrete hydrogen ions in the presence of metabolic acidosis. Over the years, knowledge of the molecular mechanisms behind acid secretion has improved, thereby greatly helping the diagnosis of dRTA. The primary or inherited form of dRTA is mostly diagnosed in infancy, childhood, or young adulthood, while the acquired secondary form, as a consequence of other disorders or medications, can happen at any age, although it is more commonly seen in adults. dRTA is not as "benign" as previously assumed, and can have several, highly variable long-term consequences. The present review indeed reports and summarizes both clinical symptoms and diagnosis, long-term outcomes, genetic inheritance, epidemiology and current treatment options, with the aim of shedding more light onto this rare disorder. Being a chronic condition, dRTA also deserves attention in the transition between pediatric and adult nephrology care, and as a rare disease it has a place in the European and Italian rare nephrological diseases network.
| S-EPMC8610947 | biostudies-literature
Project description:[1] Lactic acidosis time course: MCF7 cells were exposed to lactic acidosis for different length of time. We used microarrays to examine the genomic programs of cells incubated under lactic acidosis for different length of time [2] Metabolic profiling: MCF7 cells were exposed to control condition, 25mM lactic acidosis, glucose deprivation (zero glucose) and hypoxia (1% oxygen level). [3] Mouse study: Lactic acidosis triggers starvation response with paradoxical induction of TXNIP through MondoA. Wild-type mouse embryo fibroblasts (MEFs) and TXNIP-null MEFs were exposed to Ctrl versus lactic acidosis conditions for 24hrs and the RNAs from cells were extracted with MiRVana kit (Ambion) and applied to Affymetrix 430A mouse chips We used microarrays to examine the genomic programs of cells incubated under different microenvironmental stresses. [1] Lactic acidosis time course: MCF7 cells were exposed to lactic acidosis for 1, 4, 12 and 24 hours. [2] Metabolic profiling: MCF7 cells were exposed to lactic acidosis, glucose deprivation and hypoxia for 4hours. [3] wild-type mouse embryo fibroblasts (MEFs) and TXNIP-null MEFs were exposed to Ctrl versus lactic acidosis conditions for 24hrs.
2010-09-27 | E-GEOD-19123 | biostudies-arrayexpress
Project description:Human Mammalian Epithelial Cells (HMEC) were exposed to different environmental stresses, including hypoxia, lactic acidosis, the combination of hypoxia and lactic acidosis, lactosis , as well as acidosis. We used microarrays to examine the genomic programs of cells incubated under different microenvironments. Experiment Overall Design: HMEC cells were exposed to different environmental stresses and RNAs were extracted and put on Affymetrix microarrays. We gathered RNAs from cells grown in regular media (control), lactic acidosis, hypoxia, the combinatino of lactic acidosis and hypoxia, lactosis, as well as acidosis.
2009-01-13 | E-GEOD-9649 | biostudies-arrayexpress
Project description:5-Amino salicylic acid (5-ASA) is a known culprit for the development of tubulointerstitial nephritis. Together with impaired kidney function, tubulointerstitial nephritis can lead to specific tubular malfunctions including distal renal tubular acidosis. Distal renal tubular acidosis is an acid-base disorder in which acid secretion in the distal part of the renal tubular system is decreased. Patients with distal renal tubular acidosis are predisposed to recurrently form calcium phosphate kidney stones. This results from the inability to acidify the urine properly as well as from a decreased citrate concentration in the urine, which is another pathognomonic feature of distal renal tubular acidosis. We present the case of a man in his late 40s with Crohn's disease who developed tubulointerstitial nephritis associated with 5-ASA leading to the development of distal renal tubular acidosis and recurrent calcium phosphate nephrolithiasis. After steroid therapy and partial recovery of kidney function, we observed an increase of citraturia in response to treatment with dapagliflozin, potentially indicating beneficial effects of sodium/glucose cotransporter 2 inhibition on the recurrence of calcium phosphate stone disease in interstitial nephritis-induced distal tubular acidosis.
| S-EPMC11238181 | biostudies-literature
Project description:Distal renal tubular acidosis (dRTA) is characterized by metabolic acidosis due to uric acid dysfunction. The aim of this study was to demonstrate the genetic diagnosis of Chinese children with dRTA by whole-exome sequencing. From Jan. 2010 to Sept. 2015, 16 children with dRTA were recruited to investigate the possibility of genetic diagnosis and to examine any genotype-phenotype relationships in these patients. Sanger sequencing was used to confirm mutations identified by whole-exome sequencing. Clinical and biological features in the patients included hyperchloremic metabolic acidosis, impaired growth, hypokalemia, nephrocalcinosis, nephrolithiasis, hypercalciuria, hypocitraturia, and rickets or osteomalacia. Seventeen mutations in the solute carrier family 4 member 1 (SLC4A1), ATPase H+ transporting V0 subunit a4 (ATP6V0A4), ATPase H+ transporting V1 subunit B1 (ATP6V1B1), WNK lysine deficient protein kinase 1 (WNK1) and the claudin 16 (CLDN16) were identified in 15 patients, and 14 of these mutations are novel. Only 1 patient was negative for any mutations. Our results demonstrate the existence of SLC4A1, ATP6V1B1, ATP6V0A4, WNK1 and CLDN16 mutations in Chinese children with dRTA and indicate that compound heterozygosity at 2 or more different but related genes can be responsible for its pathogenesis. This study also indicates that whole-exome sequencing is a labor and cost-effective means of analyzing dRTA-associated genes.
| S-EPMC6962865 | biostudies-literature