Homozygous and compound heterozygous mutations in the ATP6V1B1 gene in patients with renal tubular acidosis and sensorineural hearing loss

Abstract

Distal renal tubular acidosis (dRTA) is characterized by the inability to excrete acid in the renal collecting ducts resulting in inappropriately alkaline urine and hyperchloremic (normal anion gap) metabolic acidosis in the context of a normal (or near-normal) glomerular filtration rate. Inborn dRTA can be due to autosomal dominant or recessive gene defects. Clinical symptoms vary from mild acidosis, incidental detection of kidney stones or renal tract calcification to severe findings such as failure to thrive, severe metabolic acidosis, and nephrocalcinosis. The majority of patients with recessive dRTA present with sensorineural hearing loss (SNHL). Few cases with abnormal widening of the vestibular aqueduct have been described with dRTA. Mutations in three different genes have been identified, namely SLC4A1, ATP6V1B1, and ATP6V0A4. Patients with mutations in the ATP6V1B1 proton pump subunit develop dRTA and in most of the cases sensorineural hearing loss early in childhood. We present two patients from two different and non-consanguineous families with dRTA and SNHL. Direct sequencing of the ATP6V1B1 gene revealed that one patient harbors two homozygous mutations and the other one is a compound heterozygous. To our knowledge, this is the first case in the literature describing homozygosity in the same dRTA gene on both alleles.

Fourteen Monogenic Genes Account for 15% of Nephrolithiasis/Nephrocalcinosis

“…In total, 20 of 50 mutations (40%) detected were novel pathogenic variants, which have not been previously reported (Human Gene Mutation Database; http:// www.hgmd.cf.ac.uk/ac/index.php). [9][10][11][12][13][14][15][16][17][18][19][20][21][22] In the pediatric subgroup of individuals with age of onset before 18 years (defined by age at first stone or age at diagnosis of NC), we identified a causative mutation in 20.8% (22 of 106) of individuals ( Figure 1A). In contrast, in the adult cohort (defined by age of onset $18 years), deleterious variants were detected in 11.4% (19 of 166) of individuals ( Figure 1A).…”

Haploinsufficiency of the Mouse Atp6v1b1 Gene Leads to a Mild Acid-Base Disturbance with Implications for Kidney Stone Disease

“…Similarly, ablation of the Atp6v1b1 or Atp6v0a4 genes in mice causes dRTA [17][18][19][20]. In both species, the absence of functional B1 or a4 H + -ATPase subunits can be associated with the development of nephrocalcinosis or -lithiasis [6,9,12,14,16,17,21]. Moreover, recent studies described that monoallelic mutations in these 2 genes can also lead to urinary acidification defects with elevated risk for nephrocalcinosis or-lithiasis [10,11,22].…”

“…Loss of the B1 or a4 H + -ATPase subunits in human causes congenital autosomal recessive dRTA with sensorineural deafness [6,9,12,[14][15][16]. Similarly, ablation of the Atp6v1b1 or Atp6v0a4 genes in mice causes dRTA [17][18][19][20].…”

“…2) which however did not reach statistical significance when compared to Atp6v1b1 +/+ . Patients with biallelic ATP6V1B1 mutations frequently develop nephrocalcinosis [9,11,12] and nephrocalcinosis has been also reported in some patients with only monoallelic ATP6V1B1 mutations [10,11]. We thus tested whether urinary calcium, phosphate and citrate excretion were different between genotypes and found no obvious difference at any of the time points tested (Tables 1 -3).…”

The Importance of the Ionic Product for Water to Understand the Physiology of the Acid-Base Balance in Humans

“…Unlike proximal RTA, patients with distal RTA maintain inappropriately alkaline urine in the presence of hyperchloremic acidosis [46, 56]. Tubulointerstitial nephropathies that injure collecting ducts, hypoaldosteronism states, and the use of amiloride or aldosterone antagonists such as spironolactone and eplerenone induce urinary loss of sodium in excess of chloride that results in plasma chloride retention relative to sodium and hyperchloremic acidosis [35].…”