RT Journal Article SR Electronic T1 Dominant negative mutation in oxalate transporter SLC26A6 associated with enteric hyperoxaluria and nephrolithiasis JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 1035 OP 1043 DO 10.1136/jmedgenet-2021-108256 VO 59 IS 11 A1 Cornière, Nicolas A1 Thomson, R Brent A1 Thauvin, Stéphanie A1 Villoutreix, Bruno O A1 Karp, Sophie A1 Dynia, Diane W A1 Burlein, Sarah A1 Brinkmann, Lennart A1 Badreddine, Alaa A1 Dechaume, Aurélie A1 Derhourhi, Mehdi A1 Durand, Emmanuelle A1 Vaillant, Emmanuel A1 Froguel, Philippe A1 Chambrey, Régine A1 Aronson, Peter S A1 Bonnefond, Amélie A1 Eladari, Dominique YR 2022 UL http://jmg.bmj.com/content/59/11/1035.abstract AB Background Nephrolithiasis (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.Methods We 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.Results We 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.Conclusion Our 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.All data relevant to the study are included in the article or uploaded as supplementary information. Not applicable.