Journal Article

Dominant negative mutation in oxalate transporter SLC26A6 associated with enteric hyperoxaluria and nephrolithiasis

Thauvin, Stéphanie, Chambrey, Régine, Vaillant, Emmanuel, Eladari, Dominique, Thomson, R Brent, Aronson, Peter S, Bonnefond, Amélie, Cornière, Nicolas, Dynia, Diane W, Villoutreix, Bruno O, Dechaume, Aurélie, Badreddine, Alaa, Brinkmann, Lennart, Durand, Emmanuelle, Burlein, Sarah, Derhourhi, Mehdi, Karp, Sophie, Froguel, Philippe

2022

Overview

BackgroundNephrolithiasis (NL) is a complex multifactorial disease affecting up to 10%–20% of the human population and causing a significant burden on public health systems worldwide. It results from a combination of environmental and genetic factors. Hyperoxaluria is a major risk factor for NL.MethodsWe used a whole exome-based approach in a patient with calcium oxalate NL. The effects of the mutation were characterised using cell culture and in silico analyses.ResultsWe identified a rare heterozygous missense mutation (c.1519C>T/p.R507W) in the SLC26A6 gene that encodes a secretory oxalate transporter. This mutation cosegregated with hyperoxaluria in the family. In vitro characterisation of mutant SLC26A6 demonstrated that Cl−-dependent oxalate transport was dramatically reduced because the mutation affects both SLC26A6 transport activity and membrane surface expression. Cotransfection studies demonstrated strong dominant-negative effects of the mutant on the wild-type protein indicating that the phenotype of patients heterozygous for this mutation may be more severe than predicted by haploinsufficiency alone.ConclusionOur study is in line with previous observations made in the mouse showing that SLC26A6 inactivation can cause inherited enteric hyperoxaluria with calcium oxalate NL. Consistent with an enteric form of hyperoxaluria, we observed a beneficial effect of increasing calcium in the patient’s diet to reduce urinary oxalate excretion.

• Publisher: BMJ Publishing Group Ltd,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Antiporters - genetics / Calcium - metabolism / Calcium oxalate / Calcium Oxalate - metabolism / Cell culture / Genetic factors / Haploinsufficiency / Humans / Hyperoxaluria / Hyperoxaluria - complications / Hyperoxaluria - genetics / Kidney stones / Life Sciences / missense / Missense mutation / Mutants / Mutation / Nephrolithiasis / Nephrolithiasis - complications / Nephrolithiasis - genetics / Nephrolithiasis - metabolism / nephrology / Novel Disease Loci / Oxalate transporter / Oxalates - metabolism / Oxalic acid / Phenotypes / Public health / Risk factors / Sulfate Transporters - genetics / urology