scholarly journals Acidosis and Deafness in Patients with Recessive Mutations in FOXI1

2017 ◽  
Vol 29 (3) ◽  
pp. 1041-1048 ◽  
Author(s):  
Sven Enerbäck ◽  
Daniel Nilsson ◽  
Noel Edwards ◽  
Mikael Heglind ◽  
Sumaya Alkanderi ◽  
...  
Keyword(s):  
Dna Binding ◽  
Inner Ear ◽  
Renal Tubular Acidosis ◽  
Cultured Cells ◽  
Collecting Duct ◽  
Sensorineural Deafness ◽  
Distal Renal Tubular Acidosis ◽  
Acid Base ◽  
Recessive Mutations ◽  
Renal Tubular

Maintenance of the composition of inner ear fluid and regulation of electrolytes and acid-base homeostasis in the collecting duct system of the kidney require an overlapping set of membrane transport proteins regulated by the forkhead transcription factor FOXI1. In two unrelated consanguineous families, we identified three patients with novel homozygous missense mutations in FOXI1 (p.L146F and p.R213P) predicted to affect the highly conserved DNA binding domain. Patients presented with early-onset sensorineural deafness and distal renal tubular acidosis. In cultured cells, the mutations reduced the DNA binding affinity of FOXI1, which hence, failed to adequately activate genes crucial for normal inner ear function and acid-base regulation in the kidney. A substantial proportion of patients with a clinical diagnosis of inherited distal renal tubular acidosis has no identified causative mutations in currently known disease genes. Our data suggest that recessive mutations in FOXI1 can explain the disease in a subset of these patients.

scholarly journals Targeted deletion of the Ncoa7 gene results in incomplete distal renal tubular acidosis in mice

2018 ◽  
Vol 315 (1) ◽  
pp. F173-F185 ◽  
Author(s):  
Maria Merkulova ◽  
Teodor G. Păunescu ◽  
Anil V. Nair ◽  
Chia-Yu Wang ◽  
Diane E. Capen ◽  
...  
Keyword(s):  
Renal Tubular Acidosis ◽  
Collecting Duct ◽  
Proton Pumping ◽  
Distal Renal Tubular Acidosis ◽  
Acid Base ◽  
Anion Exchanger 1 ◽  
Targeted Deletion ◽  
Kidney Morphology ◽  
Renal Tubular

We recently reported that nuclear receptor coactivator 7 (Ncoa7) is a vacuolar proton pumping ATPase (V-ATPase) interacting protein whose function has not been defined. Ncoa7 is highly expressed in the kidney and partially colocalizes with the V-ATPase in collecting duct intercalated cells (ICs). Here, we hypothesized that targeted deletion of the Ncoa7 gene could affect V-ATPase activity in ICs in vivo. We tested this by analyzing the acid-base status, major electrolytes, and kidney morphology of Ncoa7 knockout (KO) mice. We found that Ncoa7 KO mice, similar to Atp6v1b1 KOs, did not develop severe distal renal tubular acidosis (dRTA), but they exhibited a persistently high urine pH and developed hypobicarbonatemia after acid loading with ammonium chloride. Conversely, they did not develop significant hyperbicarbonatemia and alkalemia after alkali loading with sodium bicarbonate. We also found that ICs were larger and with more developed apical microvilli in Ncoa7 KO compared with wild-type mice, a phenotype previously associated with metabolic acidosis. At the molecular level, the abundance of several V-ATPase subunits, carbonic anhydrase 2, and the anion exchanger 1 was significantly reduced in medullary ICs of Ncoa7 KO mice, suggesting that Ncoa7 is important for maintaining high levels of these proteins in the kidney. We conclude that Ncoa7 is involved in IC function and urine acidification in mice in vivo, likely through modulating the abundance of V-ATPase and other key acid-base regulators in the renal medulla. Consequently, mutations in the NCOA7 gene may also be involved in dRTA pathogenesis in humans.

Glue-sniffing and distal renal tubular acidosis: sticking to the facts.

1991 ◽  
Vol 1 (8) ◽  
pp. 1019-1027 ◽  
Author(s):  
E J Carlisle ◽  
S M Donnelly ◽  
S Vasuvattakul ◽  
K S Kamel ◽  
S Tobe ◽  
...  
Keyword(s):  
Metabolic Acidosis ◽  
Renal Tubular Acidosis ◽  
Extracellular Fluid ◽  
Distal Renal Tubular Acidosis ◽  
Anion Gap ◽  
Acid Base ◽  
Major Question ◽  
The Subject ◽  
Renal Tubular ◽  
Sodium And Potassium

An index case is presented to introduce the subject of the acid-base and electrolyte abnormalities resulting from toluene abuse. These include metabolic acidosis associated with a normal anion gap and excessive loss of sodium and potassium in the urine. The major question addressed is, what is the basis for the metabolic acidosis? Overproduction of hippuric acid resulting from the metabolism of toluene plays a more important role in the genesis of the metabolic acidosis than was previously believed. This conclusion is supported by the observation that the rate of excretion of ammonium was not low during metabolic acidosis in six of eight patients, suggesting that distal renal tubular acidosis was not an important acid-base abnormality in most cases where ammonium was measured. The excretion of hippurate in the urine unmatched by ammonium also mandates an enhanced rate of excretion of the cations, sodium and potassium. The loss of sodium causes extracellular fluid volume contraction and a fall in the glomerular filtration rate, which may transform the normal anion gap type of metabolic acidosis into one with a high anion gap (accumulation of hippurate and other anions). Continuing loss of potassium in the urine leads to hypokalemia. An understanding of the metabolism of toluene provides the basis for the unusual biochemical abnormalities seen with abuse of this solvent.

scholarly journals Endolymphatic Sac Enlargement in a Girl with a Novel Mutation for Distal Renal Tubular Acidosis and Severe Deafness

2012 ◽  
Vol 2012 ◽  
pp. 1-4 ◽  
Author(s):  
Rink Nikki ◽  
Bitzan Martin ◽  
O'Gorman Gus ◽  
Nagel Mato ◽  
Torban Elena ◽  
...  
Keyword(s):  
Inner Ear ◽  
Renal Tubular Acidosis ◽  
Hearing Aids ◽  
Novel Mutation ◽  
Distal Renal Tubular Acidosis ◽  
Endolymphatic Sac ◽  
Compound Heterozygous ◽  
Cerebral Magnetic Resonance Imaging ◽  
Renal Tubular ◽  
The Right

Hereditary distal renal tubular acidosis (dRTA) is caused by mutations of genes encoding subunits of the H+-ATPase (ATP6V0A4 and ATP6V1B1) expressed inα-intercalated cells of the distal renal tubule and in the cochlea. We report on a 2-year-old girl with distal RTA and profound speech delay which was initially misdiagnosed as autism. Genetic analysis showed compound heterozygous mutations with one known and one novel mutation of the ATP6V1B1 gene; cerebral magnetic resonance imaging (MRI) revealed bilateral enlargement of the endolymphatic sacs of the inner ear. With improved cooperation, audiometric testing showed that hearing loss was most profound on the right, where endolymphatic sac enlargement was greatest, demonstrating a clear link between the degree of deafness and the degree of inner ear abnormality. This case indicates the value of MRI for diagnosis of inner ear involvement in very young children with distal RTA. Although citrate therapy quickly corrects the acidosis and restores growth, early diagnosis of deafness is crucial so that hearing aids can be used to assist acquisition of speech and to provide enough auditory nerve stimulation to assure the affected infants remain candidates for cochlear implantation.

Complicated pregnancies in inherited distal renal tubular acidosis: importance of acid-base balance

2016 ◽  
Vol 30 (3) ◽  
pp. 455-460 ◽  
Author(s):  
Harald Seeger ◽  
Peter Salfeld ◽  
Rüdiger Eisel ◽  
Carsten A. Wagner ◽  
Nilufar Mohebbi
Keyword(s):  
Renal Tubular Acidosis ◽  
Distal Renal Tubular Acidosis ◽  
Acid Base Balance ◽  
Acid Base ◽  
Base Balance ◽  
Renal Tubular

scholarly journals Preservation of intercalated cell H(+)-ATPase in two patients with lupus nephritis and hyperkalemic distal renal tubular acidosis.

1997 ◽  
Vol 8 (7) ◽  
pp. 1109-1117
Author(s):  
B Bastani ◽  
D Underhill ◽  
N Chu ◽  
R D Nelson ◽  
L Haragsim ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Renal Tubular Acidosis ◽  
Frozen Section ◽  
Collecting Duct ◽  
Rat Kidney ◽  
Distal Renal Tubular Acidosis ◽  
Intercalated Cells ◽  
Urine Ph ◽  
Control Serum ◽  
Renal Tubular

In patients with Sjögren's syndrome and a secretory-defect distal renal tubular acidosis (dRTA), absence of vacuolar H(+)-ATPase from collecting duct intercalated cells has been reported. The H(+)-ATPase was examined in two patients with lupus nephritis and hyperkalemic (presumed voltage defect) dRTA. Both patients had a positive urine anion gap, alkaline urine despite acidemia, no rise in urine PCO2 with alkaluria, a urine pH > 5.5, and urine potassium excretion rate not significantly increased after 80 mg of intravenous furosemide. In both patients, immunocytochemistry of renal biopsy frozen sections with an anti-H(+)-ATPase monoclonal antibody showed bright staining of the proximal tubule brush border and collecting duct intercalated cells. In one patient, routine immunofluorescence analysis of a frozen section of her kidney biopsy with antihuman IgG showed staining of the collecting duct, indicative of autoantibodies to this segment. Moreover, rat kidney sections incubated with her serum showed labeling of the intercalated cells. On immunoblots of human kidney microsomal membranes performed with serum from both patients, an immunoreactive polypeptide was observed at M(r) approximately 56 kD that was not seen with control serum. Neither patient's sera reacted with affinity-purified bovine H(+)-ATPase or with lysates from 293 cell fibroblasts in which either of both isoforms of the human H(+)-ATPase B subunit (56 kD) were expressed. These findings demonstrate that the spectrum of dRTA includes the preservation of H(+)-ATPase in intercalated cells, in patients with presumed voltage defect dRTA. Moreover, some patients may have autoantibodies to the intercalated cells that are not directed to subunits of the H(+)-ATPase.

scholarly journals Clinical and Molecular Findings in a Moroccan Family with Primary Distal Renal Tubular Acidosis and Deafness by Mutation of ATP60A4 Gene: Case Report

2021 ◽  
pp. 9-14
Author(s):  
Nadia Mebrouk ◽  
Rachid Abilkassem ◽  
Aomar Agadr
Keyword(s):  
Metabolic Acidosis ◽  
Renal Tubular Acidosis ◽  
Collecting Duct ◽  
Gene Mutations ◽  
Recessive Gene ◽  
Failure To Thrive ◽  
Distal Renal Tubular Acidosis ◽  
Tubular Dysfunction ◽  
Dominant Form ◽  
Renal Tubular

Primary distal renal tubular acidosis (dRTA) is a rare genetic disease characterized by distal tubular dysfunction leading to metabolic acidosis and alkaline urine.  It is associated with impaired acid excretion by the intercalated cells in the renal collecting duct.  dRTA is developed during the first months of life and the main clinical and biologic features are failure to thrive, vomiting, dehydration, anorexia, hyperchloremic non-anion gap metabolic acidosis, hypocitraturia, hypercalciuria and nephrocalcinosis.  The disease is caused by defects in genes involved in urinary distal acidification: ATP6V0A4 and ATP6V1B1 for the recessive form, and SLC4A1 for the dominant form.  Some dRTA cases due to recessive gene mutations are associated with hearing impairment. We report the case of two siblings with dRTA, and early-onset SNHL, due to ATP6V0A4 mutations, and whose parents are heterozygous carriers of ATP6V0A4 mutations.

scholarly journals Absence of vacuolar H(+)-ATPase pump in the collecting duct of a patient with hypokalemic distal renal tubular acidosis and Sjögren's syndrome.

1995 ◽  
Vol 6 (2) ◽  
pp. 295-301
Author(s):  
P E DeFranco ◽  
L Haragsim ◽  
P G Schmitz ◽  
B Bastani
Keyword(s):  
Renal Biopsy ◽  
Renal Tubular Acidosis ◽  
Collecting Duct ◽  
Band 3 ◽  
Distal Renal Tubular Acidosis ◽  
Hydrogen Ion ◽  
Intercalated Cells ◽  
Band 3 Protein ◽  
Ion Secretion ◽  
Renal Tubular

Distal renal tubular acidosis (dRTA) is a common complication of autoimmune connective tissue diseases. The underlying pathophysiology of renal tubular acidosis in these syndromes is frequently characterized by impaired hydrogen ion secretion, i.e., secretory defect dRTA. However, the precise molecular events leading to this disturbance remain poorly understood. An opportunity was recently afforded to examine the ultrastructural features of the collecting duct in a patient with Sjögren's syndrome and secretory defect dRTA. Immunocytochemical analysis of a renal biopsy obtained 12 months after the patient's initial presentation demonstrated a complete absence of vacuolar H(+)-ATPase in the collecting duct. Antibodies to the 31- and 56-kd kidney-specific subunits of the H(+)-ATPase pump were used to characterize pump distribution. Interestingly, although antiserum to the CI-:HCO3- anion exchanger (band-3 protein) reacted strongly with normal human kidney and the patient's red blood cells, no immunoreactivity was observed in the patient's collecting duct epithelium. Importantly, electron microscopy of the patient's renal biopsy specimen disclosed cells that ultrastructurally were indistinguishable from intercalated cells. These results suggest that the functional basis of impaired hydrogen ion secretion in this patient was secondary to the absence of intact H(+)-ATPase pumps rather than defective pump function or distribution. The presence of intercalated cells ultrastructurally, but the absence of discernible staining for band-3 protein and H(+)-ATPase, also suggests that the defect in proton secretion may represent a defect involving the assembly of at least two of the ion transport pumps essential for the normal maintenance of acid-base homeostasis by the intercalated cells.(ABSTRACT TRUNCATED AT 250 WORDS)

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