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Published on: August 15, 2019
Phenotypic variability in distal acidification defects associated with WDR72 mutations
Priyanka Khandelwal1, Mahesh V1, Vijay Prakash Mathur2
1Division of Nephrology, Department of Pediatrics, ICMR Center for Advanced Research in Nephrology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.
Background:
Distal renal tubular acidosis (RTA) is typically caused by defects in ATP6V0A4, ATP6V1B1, and SLC4A1, accounting for 60-80% of patients. Genes recently implicated include FOXI1, ATP6V1C2, and WDR72, of which WDR72 is associated with dental enamel defects.
Methods:
We describe 4 patients, from three unrelated consanguineous families, with RTA and amelogenesis imperfecta. Distal tubular acidification was evaluated by furosemide-fludrocortisone test, urine-to-blood PCO2 gradient and fractional excretion of bicarbonate. Exome sequencing was performed using a panel of genes implicated in human disease.
Results:
Patients had polyuria, hypokalemia, hypercalciuria, and nephrocalcinosis, but metabolic acidosis varied in severity. Although all patients acidified urine to pH < 5.3 during furosemide-fludrocortisone test, urine-to-blood PCO2 gradient was < 20 mmHg during bicarbonate loading. All patients had transient proximal tubular dysfunction with urinary losses of phosphate and beta-2-microglobulin, and generalized aminoaciduria. Homozygous pathogenic truncating variants in WDR72 was detected in all probands.
Conclusion:
Patients with WDR72 mutations show mild rate-dependent distal RTA with variable metabolic acidosis, and intact ability to acidify the urine on provocative testing. Concomitant proximal tubular dysfunction may be present. Mutations in WDR72 should be considered in patients with suspected distal RTA, especially if associated with dental defects.
Insights
Mutations in the WDR72 gene cause distal renal tubular acidosis (RTA) and dental enamel defects. This finding expands the genetic causes of RTA, particularly in patients with amelogenesis imperfecta.
Area of Science:
- Genetics
- Nephrology
- Pediatrics
Background:
- Distal renal tubular acidosis (RTA) is often caused by mutations in ATP6V0A4, ATP6V1B1, and SLC4A1.
- WDR72 is a recently identified gene associated with dental enamel defects and RTA.
Purpose of the Study:
- To investigate the genetic basis of RTA in patients with amelogenesis imperfecta.
- To identify novel genetic causes of distal RTA.
Main Methods:
- Described four patients from three consanguineous families with RTA and amelogenesis imperfecta.
- Evaluated distal tubular acidification using furosemide-fludrocortisone testing and urine-to-blood PCO2 gradient.
- Performed exome sequencing on a panel of disease-implicated genes.
Main Results:
- All patients presented with polyuria, hypokalemia, hypercalciuria, and nephrocalcinosis, with variable metabolic acidosis.
- Despite intact urine acidification capacity, patients exhibited impaired bicarbonate reabsorption.
- Homozygous pathogenic truncating variants in WDR72 were identified in all affected individuals.
Conclusions:
- WDR72 mutations result in mild distal RTA with variable metabolic acidosis and potential proximal tubular dysfunction.
- WDR72 should be considered in the genetic evaluation of distal RTA, especially when dental defects are present.
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