Phenotypic variability in distal acidification defects associated with WDR72 mutations
- PDF / 848,628 Bytes
- 7 Pages / 595.276 x 790.866 pts Page_size
- 44 Downloads / 200 Views
ORIGINAL ARTICLE
Phenotypic variability in distal acidification defects associated with WDR72 mutations Priyanka Khandelwal 1 & Mahesh V 1 & Vijay Prakash Mathur 2 & Sumantra Raut 1 & Thenral S. Geetha 3 & Sandhya Nair 3 & Pankaj Hari 1 & Aditi Sinha 1 & Arvind Bagga 1 Received: 19 April 2020 / Revised: 21 July 2020 / Accepted: 26 August 2020 # IPNA 2020
Abstract 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. Keywords Amelogenesis imperfecta . Nephrocalcinosis . Renal tubular acidosis . Fanconi syndrome . Hypokalemia . Children
Introduction Distal renal tubular acidosis (RTA), characterized by impaired urinary acidification and hyperchloremic metabolic acidosis, presents with hypokalemia, hypercalciuria, and nephrocalcinosis [1, 2]. The vacuolar H+-ATPases (V-type ATPase), located in alpha intercalated cells of late distal tubule and collecting duct, actively secrete protons into the lumen and are the chief mediators of distal acidification [3]. The majority of distal RTA is due to defects in the V0 (membrane-bound) and V1 (cytoplasmic) subunits * Aditi Sinha [email protected] 1
Division of Nephrology, Department of Pediatrics, ICMR Center for Advanced Research in Nephrology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India
2
Center for Dental Education and Research, All India Institute of Medical Sciences, New Delhi, India
3
Medgenome Labs, Bommasandra, Bangalore, India
encoded by ATP6V0A4 and ATP6V1B1. Distal RTA associated with hereditary ovalocytosis results from defects in the bicarbonate/chloride exchanger encoded by SLC4A1. While genetic defects in the
Data Loading...
