Clinical characteristics.

Individuals with hereditary distal renal tubular acidosis (dRTA) typically present in infancy with poor weight gain and growth deficiency, although later presentations can occur, especially in individuals with autosomal dominant SLC4A1-related dRTA. Initial clinical manifestations can also include emesis, polyuria, polydipsia, constipation, diarrhea, decreased appetite, and episodes of dehydration. Electrolyte manifestations include hyperchloremic non-anion gap metabolic acidosis and hypokalemia. Renal complications of hereditary dRTA include nephrocalcinosis, nephrolithiasis, medullary cysts, and impaired kidney function. Additional manifestations include bone demineralization (rickets, osteomalacia), sensorineural hearing loss (in ATP6V0A4-, ATP6V1B1-, and FOXI1-related dRTA), hereditary hemolytic anemia (in some individuals with SLC4A1-related dRTA), and amelogenesis imperfecta (in WDR72-related dRTA).

Diagnosis/testing.

The diagnosis of hereditary dRTA is established in a proband with dRTA and biallelic pathogenic variants in ATP6V0A4, ATP6V1B1, FOXI1, or WDR72, a heterozygous or biallelic pathogenic variants in SLC4A1, or specific heterozygous pathogenic variants in ATP6V1B1 (affecting codon p.Arg394) identified by molecular genetic testing.

Management.

Targeted therapies: Oral alkaline therapy to correct metabolic acidosis and hypokalemia with additional potassium chloride as needed. ADV7103 is a combination controlled-release potassium bicarbonate and potassium citrate medication approved in Europe that allows less frequent dosing.

Supportive care: Standard treatments for other possible manifestations including sensorineural hearing, hemolytic anemia, and amelogenesis imperfecta.

Surveillance: Fasting venous blood gas or total CO₂ prior to alkali dose in rapidly growing infants and children at least every three to four months, and at least every six months in older individuals. Serum creatinine, urea, sodium, potassium, chloride, calcium, phosphate, alkaline phosphatase, and albumin in rapidly growing infants and young children at least every three to four months, and at least every six to 12 months in stable older children and adults. Urinalysis and urine creatinine, sodium, potassium, calcium, and citrate annually and more frequently when adjusting treatment. Annual renal ultrasound to evaluate for nephrocalcinosis, urolithiasis, and cysts in asymptomatic individuals. Growth assessment with calculation of body mass index in infants at least every three months, and in older children at least every six months until achievement of final height. Bone densitometry as needed. Audiometry annually in at-risk individuals. Assessment for hemolytic anemia and dental assessment as needed in at-risk individuals.

Agents/circumstances to avoid: Potassium-sparing diuretics should be used with caution or avoided.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.

Pregnancy management: Women with hereditary dRTA may develop severe metabolic acidosis and hypokalemia during pregnancy, especially when complicated by hyperemesis gravidarum. Close monitoring of women with hereditary dRTA during pregnancy is necessary.

Genetic counseling.

Hereditary distal renal tubular acidosis caused by loss-of-function variants in ATP6V0A4, ATP6V1B1, SLC4A1, FOXI1, or WDR72 is inherited in an autosomal recessive manner. Hereditary dRTA caused by dominant-negative variants in SLC4A1 or heterozygous pathogenic variants in ATP6V1B1 affecting the specific amino acid p.Arg394 are inherited in an autosomal dominant manner.

Autosomal recessive inheritance: If both parents are known to be heterozygous for an autosomal recessive dRTA-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.

Autosomal dominant inheritance: Each child of an individual with autosomal dominant dRTA has a 50% chance of inheriting the pathogenic variant.

Once the hereditary dRTA-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

Hereditary dRTA should be suspected in probands with the following clinical, laboratory, and imaging findings and family history.

Clinical findings

• Poor weight gain and growth deficiency in childhood
• Sensorineural hearing loss
• Symptoms of hypokalemia, including muscle weakness and muscle cramps
• Bone manifestations (10%-23%): osteomalacia (in adults), refractory rickets (in children), fractures, bone pain
• Exclusion of systemic diseases (e.g., autoimmune disorders) and medications causing dRTA

Laboratory findings

• Hyperchloremic non-anion gap metabolic acidosis in the absence of gastrointestinal losses
• Hypokalemia (blood potassium level <3.5 mEq/L)
• Hypobicarbonatemia (blood bicarbonate levels <20 mEq/L in infants and <22 mEq/L in older children), but with normal fractional excretion of bicarbonate when blood bicarbonate is normal following alkali administration
• Absence of a negative urine anion gap (UAG) in an individual with metabolic acidosis. Calculation of the UAG (U_AG = [Na⁺]_U + [K⁺]_U − [Cl⁻]_U) can help to distinguish between hereditary forms of proximal and distal RTA.
• Elevated urine calcium
• Decreased urine citrate
• Failure to acidify the urine (urine pH always >5.3):
  • After an ammonium chloride challenge (100 mg/kg) [Wrong & Davies 1959]; OR
  • When increased distal delivery of sodium is induced, via the coadministration of a mineralocorticoid (e.g., fludrocortisone 0.02 mg/kg) and furosemide (0.5 mg/kg) [Walsh et al 2007, Shavit et al 2016]; OR
  • In an individual who presents with spontaneous acidosis.

Imaging findings

• Renal ultrasound. Nephrocalcinosis is almost universal; nephrolithiasis is less common but does occur. Medullary cysts may be detected, typically in later childhood or in adults [Igarashi et al 1991, Besouw et al 2017], including medullary sponge kidney [van den Berg et al 2024].
• Plain radiographs of the bones may show rachitic changes [Mathew et al 2025].
• Bone densitometry examination may show decreased bone density in children and adults [Domrongkitchaiporn et al 2001, Bertholet-Thomas et al 2023].
• CT examination of the inner ear may demonstrate dilatation of the vestibular aqueduct in individuals with hereditary dRTA associated with hearing loss [Palazzo et al 2017].

Family history is consistent with autosomal recessive (e.g., affected sibs and/or parental consanguinity) or autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

Clinical Description

Individuals with hereditary distal renal tubular acidosis (dRTA) typically present in infancy with poor weight gain and growth deficiency, although later presentations can occur, especially in individuals with autosomal dominant SLC4A1-related dRTA. Initial clinical manifestations may also include emesis, polyuria, polydipsia, constipation, diarrhea, decreased appetite, episodes of dehydration, and refractory rickets [Besouw et al 2017, Palazzo et al 2017, Mathew et al 2025].

Electrolyte manifestations include hypokalemia and hyperchloremic non-anion gap metabolic acidosis with inappropriately elevated urine pH (which may lead to secondary tachypnea if severe [Besouw et al 2017, Palazzo et al 2017]). Some individuals may present with evidence of proximal tubular dysfunction (e.g., amino aciduria, decreased reabsorption of phosphate, and low-molecular-weight proteinuria); however, this resolves with correction of the acidosis [Besouw et al 2017].

Renal complications in dRTA include nephrocalcinosis, nephrolithiasis, medullary cysts – some individuals having radiologic findings compatible with medullary sponge kidney [van den Berg et al 2024] – and impaired kidney function, which may begin in childhood or adolescence [Igarashi et al 1991, Besouw et al 2017].

Nephrocalcinosis, typically bilateral, results from calcium deposition in the renal parenchyma. In a large, mostly European cohort of 340 individuals with dRTA, more than 90% of individuals with molecularly confirmed hereditary dRTA had nephrocalcinosis [Lopez-Garcia et al 2019]. The occurrence appears to increase with age and with later onset of alkalinizing therapy.

Medullary cysts develop in many individuals during childhood or in adulthood, likely secondary to hypokalemia [Igarashi et al 1991, Besouw et al 2017].

A mild-to-moderate decrease in glomerular filtration rate can occur; this increases in prevalence with age but may be present in childhood [Besouw et al 2017, Palazzo et al 2017].

Hypokalemia (blood potassium level <3.5 mEq/L) is found in the majority of individuals with dRTA [Rodríguez-Soriano 2002, Pirojsakul et al 2011]. Individuals with ATP6V1B1- or ATP6V0A4-related dRTA tend to have more severe hypokalemia than individuals with autosomal dominant SLC4A1-related dRTA [Karet 2002, Alonso-Varela et al 2018]. Symptoms of hypokalemia include muscle weakness and muscle cramps [Nilwarangkur et al 1990, Pirojsakul et al 2011]. Paralysis and respiratory depression as a result of muscle weakness may occur with severe hypokalemia. Renal cysts are likely related to hypokalemia, although its pathogenic mechanism has not been specifically studied in dRTA and its clinical significance is ill defined [Santos & Gil-Peña 2023].

Skeletal manifestations. The metabolic acidosis in dRTA results in the release of bicarbonate and phosphate – which are complexed with calcium – from bone. These salts act as alkalizing buffers to promote restoration of physiologic blood pH [Bushinsky & Krieger 2022].

Bone demineralization can cause rickets in children and osteomalacia in adults. These conditions increase the risk of fractures and may cause bone pain. The frequency and severity of bone findings reported in the literature vary significantly [Santos & Gil-Peña 2023]. Rickets can cause bone deformities; ambulation may be impaired as a result of leg deformities [Mathew et al 2025]. In a recently published series from India reporting 72 individuals age ≤18 years who presented with non-nutritional rickets and normal kidney function, 34 (47%) were diagnosed with dRTA, with identification of dRTA-related pathogenic variants in 14 individuals [Mathew et al 2025]. The reported prevalence of osteomalacia in adults ranges from 10% to 23% [Nilwarangkur et al 1990]. Low bone mass has been commonly reported in individuals of Thai descent with dRTA [Domrongkitchaiporn et al 2001]. Alkaline therapy has been shown to improve bone mineral density in these individuals [Domrongkitchaiporn et al 2002].

Growth deficiency. Distal RTA is often diagnosed during the evaluation of infants or young children with failure to thrive (principally manifesting as poor linear growth with normal weight for height) [Besouw et al 2017]. The majority of children with dRTA have short stature prior to adequate alkaline therapy [Besouw et al 2017]. The height deficit at diagnosis can be severe [Bajpai et al 2005]. Children treated with adequate alkaline therapy have improved growth velocity and catch-up growth is common, frequently allowing achievement of a normal height [Besouw et al 2017, Lopez-Garcia et al 2019, Santos & Gil-Peña 2023].

Sensorineural hearing loss occurs in individuals with pathogenic variants in ATP6V0A4, ATP6V1B1, or FOXI1. Both childhood onset and adult onset can occur; the hearing loss can be profound [Karet et al 1999, Vargas-Poussou et al 2006, Enerbäck et al 2018]. Increased severity and earlier-onset hearing loss is more common in individuals with autosomal recessive ATP6V1B1-related dRTA. Pathogenic variants in FOXI1 are usually associated with early-onset hearing loss. Progression or appearance of deafness is not prevented by medical treatment. Hearing impairment is treated with hearing aids or cochlear implants when necessary.

Hematologic manifestations. A small number of individuals with SLC4A1-related dRTA will also have hereditary hemolytic anemia. Pathogenic variants causing both dRTA and hemolytic anemia most commonly occur in Southeast Asia and have also been reported in families in the Middle East and India. The combination of dRTA and hemolytic anemia usually presents in infants and children with biallelic pathogenic variants [Fawaz et al 2012, Khositseth et al 2012]. In one series including 78 affected individuals, hemoglobin values ranged from 4.4 to 15.7 g/dL [Khositseth et al 2012]. Biallelic SLC4A1 pathogenic variants can result in morphologic changes in erythrocytes. These altered erythrocytes are vulnerable to hemolysis under conditions of metabolic acidosis. Alkaline therapy is associated with correction of anemia and reticulocytosis [Khositseth et al 2008]. Affected individuals also respond to transfusion and iron therapy [Khositseth et al 2012].

Amelogenesis imperfecta. Individuals with WDR72-related dRTA can have enamel discoloration and loss of enamel following tooth eruption with increased risk of chipping or cracked teeth [Deepthi et al 2025].

Heterozygotes for pathogenic variants in genes typically associated with autosomal recessive complete dRTA

• Heterozygous ATP6V1B1 pathogenic variants have been identified in a few individuals with mild renal acidification defects that do not result in altered blood pH; these individuals are said to have incomplete dRTA [Zhang et al 2014, Dhayat et al 2016]. The diagnosis can be made with an ammonium chloride or fludrocortisone/furosemide challenge, as these individuals also fail to adequately acidify their urine. These individuals also commonly have hypercalciuria and kidney stones.
• Although no manifestations of dRTA have been reported in heterozygous parents of children with biallelic SLC4A1 pathogenic variants, a few families have been reported in which the heterozygous parents of children with biallelic SLC4A1 c.2573C>A (p.Ala858Asp) pathogenic variants and dRTA with hemolytic anemia (with striking acanthocytosis of red blood cells) had only mild acanthocytosis [Fawaz et al 2012].

Phenotype Correlations by Gene

ATP6V0A4 may be associated with a more severe metabolic acidosis and later onset of deafness [Karet et al 1999, Stover et al 2002, Vargas-Poussou et al 2006, Besouw et al 2017].

ATP6V1B1 biallelic variants are associated with symptom onset in infancy or childhood, and deafness typically with onset in infancy.

FOXI1 is associated with autosomal recessive dRTA and early-onset deafness [Enerbäck et al 2018].

SLC4A1 is typically associated with a milder form of dRTA; affected individuals may have a compensated hyperchloremic metabolic acidosis (low serum bicarbonate but normal pH) [Besouw et al 2017]. Symptom onset occurs in childhood or later, with less impact on growth than in the autosomal recessive forms.

WDR72 is associated with autosomal recessive dRTA and amelogenesis imperfecta; the vast majority of affected individuals are of Indian ancestry [Deepthi et al 2025].

Genotype-Phenotype Correlations

No clinically relevant genotype-phenotype correlations for hereditary dRTA have been identified.

Nomenclature

Hereditary dRTA includes both "complete RTA" and "incomplete RTA." Complete RTA refers to a failure to excrete acid leading to metabolic acidosis. Incomplete RTA refers to a failure to excrete acid in the absence of frank metabolic acidosis and is a mild renal acidification defect.

Hereditary dRTA may also be referred to as secretory-defect dRTA.

Prevalence

The prevalence of hereditary dRTA is unclear, although it is certainly rare (~350 individuals have been reported in the literature). A retrospective analysis of records coded in the Clinical Practice Research Datalink (CPRD) of the United Kingdom estimated a prevalence of dRTA in 2017 between 0.46 (diagnosed) and 1.60 (diagnosed and suspected) in 10,000 people; 22% of these individuals had presumed hereditary dRTA [Bianic et al 2021].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with hereditary dRTA, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended.

Agents/Circumstances to Avoid

Potassium-sparing diuretics should be used with caution or avoided altogether.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Evaluations can include:

• Molecular genetic testing if the pathogenic variant(s) in the family are known;
• Venous blood gas or total CO₂ and plasma electrolytes if the pathogenic variant(s) in the family are not known.

At-risk newborns should undergo assessment of acid-base status and serum electrolytes, specifically blood gas analysis and plasma electrolytes, to identify a normal anion gap metabolic acidosis and hypokalemia pending the results of molecular genetic testing for known familial pathogenic variant(s).

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Women with hereditary dRTA may develop severe metabolic acidosis and hypokalemia during pregnancy, especially when complicated by hyperemesis gravidarum. Close monitoring of women with hereditary dRTA during pregnancy is necessary [Seeger et al 2017].

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Hereditary distal renal tubular acidosis (dRTA) caused by loss-of-function variants in ATP6V0A4, ATP6V1B1, SLC4A1, FOXI1, or WDR72 is inherited in an autosomal recessive manner.

Hereditary dRTA caused by dominant-negative variants in SLC4A1 is inherited in an autosomal dominant manner.

Hereditary dRTA caused by heterozygous pathogenic variants in ATP6V1B1 affecting the specific amino acid p.Arg394 is inherited in an autosomal dominant manner [Daenen et al 2025].

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for an autosomal recessive dRTA-related pathogenic variant.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an autosomal recessive dRTA-related pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• The heterozygous parents of a child with autosomal recessive dRTA are usually asymptomatic and are not at risk of developing complete dRTA.
  • Heterozygous ATP6V1B1 pathogenic variants have been identified in a few individuals with incomplete dRTA (mild renal acidification defects that do not result in altered blood pH) [Dhayat et al 2016]. Note: These are different ATP6V1B1 pathogenic variants than the variants affecting codon p.Arg394 that cause autosomal dominant dRTA.
  • Although no manifestations of dRTA have been reported in heterozygous parents of children with biallelic SLC4A1 pathogenic variants, a few families have been reported in which the heterozygous parents of children with biallelic SLC4A1 c.2573C>A (p.Ala858Asp) pathogenic variants and dRTA with hemolytic anemia (with striking acanthocytosis of red blood cells) had only mild acanthocytosis [Fawaz et al 2012].

Sibs of a proband

• If both parents are known to be heterozygous for an autosomal recessive dRTA-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants.
• The heterozygous sibs of a proband with autosomal recessive dRTA are usually asymptomatic and are not at risk of developing complete dRTA.
  • Heterozygous ATP6V1B1 pathogenic variants have been identified in a few individuals with incomplete dRTA (mild renal acidification defects that do not result in altered blood pH) [Dhayat et al 2016].
  • No manifestations of dRTA have been reported in heterozygous sibs of probands with biallelic SLC4A1 pathogenic variants.

Offspring of a proband. The offspring of an individual with autosomal recessive dRTA are obligate heterozygotes for a dRTA-related pathogenic variant.

Other family members. Each sib of the proband's parents has a 50% risk of being heterozygous for a hereditary dRTA-related pathogenic variant.

Heterozygote detection. Heterozygote testing for at-risk relatives requires prior identification of the hereditary dRTA-related pathogenic variants in the family.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Most individuals diagnosed with autosomal dominant SLC4A1-related dRTA have the disorder as the result of a de novo pathogenic variant [Gómez et al 2016, Palazzo et al 2017, Alonso-Varela et al 2018, Zhang et al 2018]. Approximately 40% of individuals (eight out of 20) with autosomal dominant ATP6V1B1-related dRTA have the disorder as the result of a de novo pathogenic variant affecting codon p.Arg394 [Daenen et al 2025].
• Very few individuals diagnosed with autosomal dominant SLC4A1-related dRTA have an affected parent. Approximately 50% of individuals diagnosed with autosomal dominant ATP6V1B1-related dRTA have an affected parent [Daenen et al 2025].
• If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members or death of the parent before the onset of symptoms. Therefore, de novo occurrence of a pathogenic variant cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [Daenen et al 2025].* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * A parent with somatic and gonadal mosaicism for an SLC4A1 pathogenic variant or an ATP6V1B1 pathogenic variant affecting codon p.Arg394 may be mildly/minimally affected.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the autosomal dominant dRTA-related pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the proband has a known autosomal dominant dRTA-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [Daenen et al 2025].
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for autosomal dominant dRTA because of the possibility of reduced penetrance in a heterozygous parent or parental gonadal mosaicism.

Offspring of a proband. Each child of an individual with autosomal dominant dRTA has a 50% chance of inheriting the autosomal dominant dRTA-related pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the hereditary dRTA-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Distal renal tubular acidosis (dRTA) is the result of a failure of the alpha intercalated cells of the connecting tubule and collecting duct to secrete H⁺. The urine is ultimately acidified in the connecting tubule / collecting duct (CNT/CD) via a V-type H⁺-ATPase, a multiprotein complex. The two most common causes of dRTA are impairment of complex members V1B1 (beta-1) and V0A4 (alpha-4), encoded by ATPV1B1 and ATPV0A4, respectively. These proteins are also expressed in the ear and are involved in hearing [Karet et al 1999, Stover et al 2002], resulting in co-occurrence of dRTA and hearing loss [Palazzo et al 2017].

Forkhead box protein I1 (FOXI1), encoded by FOXI1, is a transcription factor present in acid-secreting epithelia, including the CNT/CD necessary for normal expression of both the V1B1 and V0A4 subunits of the H⁺-ATPase.

In order to secrete acid into the pro-urine, H⁺ must first be generated in the alpha intercalated cell of the CNT/CD. H⁺ is generated from carbon dioxide and water, a process catalyzed by carbonic anhydrase II, encoded by CA2 (see Differential Diagnosis), which also produces bicarbonate (HCO₃^-). In order to continue to provide H⁺, the bicarbonate is effluxed from the cell across the basolateral membrane, adding to the pool of circulating buffer in the blood. Transport of HCO₃^- across the basolateral membrane is mediated by the anion exchanger (AE1) encoded by SLC4A1, pathogenic variants in which also cause dRTA [Karet et al 1998].

The role of WD repeat-containing protein 72 (WDR72), encoded by WDR72, in cell biology/physiology is not clear. Based on molecular homology modeling, it has been proposed that the protein product contributes to the trafficking of membrane proteins, and thus its altered function could inhibit the proper trafficking of one of the gene products described above. Consistent with this, WDR72 binds to H⁺-ATPase subunits [Merkulova et al 2015].

Mechanism of disease causation

• Pathogenic variations in ATP6V0A4, ATP6V1B1, SLC4A1, FOXI1, and WDR72 associated with autosomal recessive dRTA are loss-of-function variants.
• Autosomal dominant disease-causing variants in SLC4A1 are dominant-negative variants.
• ATP6V1B1 pathogenic variants affecting codon p.Arg394 cause autosomal dominant disease and act in a dominant-negative manner.

Author Notes

R Todd Alexander is the Canada Research Chair in Renal Epithelial Transport Physiology.

Acknowledgments

The Laboratory of R Todd Alexander is funded by the Natural Sciences and Engineering Research Council (NSERC) of Canada, the Canadian Institutes of Health Research (CIHR), the Women and Children's Health Research Institute (WCHRI), and the Kidney Foundation of Canada.

F Santos and H Gil-Peña thank the research support from the Fondo de Investigación Sanitaria, Instituto de Salud Carlos III of Spain, and the Fundación Nutrición y Crecimiento.

Author History

R Todd Alexander, MD, PhD (2019-present)
Helena Gil-Peña, PhD (2019-present)
Larry A Greenbaum, MD, PhD (2019-present)
Linda Law, MD, MBA; Advicenne (2019-2025)
Fernando Santos, MD, PhD (2019-present)

Revision History

• 3 April 2025 (sw) Comprehensive updated posted live
• 10 October 2019 (sw) Review posted live
• 15 January 2019 (rta) Original submission

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