Distal renal tubular acidosis caused by tryptophan‐aspartate repeat domain 72 (WDR72) mutations

Abstract

Hereditary distal renal tubular acidosis (dRTA) is a rare genetic disease that is caused by mutations in SLC4A1, ATP6V1B1, or ATP6V0A4. However, there are many families with hereditary dRTA in whom the disease-causing genes are unknown. Accordingly, we performed whole exome sequencing and genetic studies of the members of a family with autosomal recessive dRTA of an unknown genetic etiology. Here, we report compound heterozygous pathogenic variations in tryptophan-aspartate repeat domain 72 (WDR72) (c.1777A>G [p.R593G] and c.2522T>A [p.L841Q]) in three affected siblings of a family with dRTA. Both variants segregated with dRTA in the family and were not observed in normal control subjects. Homologous modeling and in silico mutagenesis indicated that R593G and L841Q alter the H-bond formations in the nearby residues, affecting the WDR72 protein structure. All these evidences indicate that the identified WDR72 variations were probably to have caused hereditary dRTA in the reported family. In addition, homozygous nonsense mutation (c.2686C>T [p.R896X]) was identified in another family, strongly supporting the causal role of WDR72 in dRTA. Based on our literature review, WDR72 mutations associated with dRTA have not been previously described. This is the first identification of pathogenic variations in WDR72 as a cause of hereditary dRTA.

Inherited Tubulopathies of the Kidney

“…In contrast to FOXI1, the discovery of WDR72 as a distal RTA disease gene was completely unexpected, illustrating the power of genetics to provide novel insights (42). Mutations in WDR72 were identified in several patients with a syndromic combination of amelogenesis imperfecta and distal RTA.…”

Mutations in RELT cause autosomal recessive amelogenesis imperfecta

“…The observation of intact genes in these vertebrates contrasts with genes that are truly specialized for amelogenesis, which become pseudogenized in these species . Recently, WDR72 defects were shown to cause AI with distal renal tubular acidosis (dRTA) . We expect further information about the range of enamel malformations and other phenotypes associated with RELT defects will be forthcoming as more RELT −/− patients are identified and the Relt −/− mice are better characterized.…”

Treatment and long-term outcome in primary distal renal tubular acidosis

“…Often referred to as type 1 RTA, it is characterised by an impaired ability of the αintercalated cells in the collecting duct to secrete protons with consequently disturbed acid-base homeostasis (1). Currently, 5 genes are recognized, mutation in which can cause dRTA: SLC4A1 (2), ATP6V0A4 (3), ATP6V1B1 (4), FOXI1 (5) and WDR72 (6). SLC4A1 encodes the anion exchanger AE1 expressed on the basolateral aspect of the intercalated cells.…”