TY - JOUR T1 - Dominant negative mutation in oxalate transporter <em>SLC26A6</em> associated with enteric hyperoxaluria and nephrolithiasis JF - Journal of Medical Genetics JO - J Med Genet SP - 1035 LP - 1043 DO - 10.1136/jmedgenet-2021-108256 VL - 59 IS - 11 AU - Nicolas Cornière AU - R Brent Thomson AU - Stéphanie Thauvin AU - Bruno O Villoutreix AU - Sophie Karp AU - Diane W Dynia AU - Sarah Burlein AU - Lennart Brinkmann AU - Alaa Badreddine AU - Aurélie Dechaume AU - Mehdi Derhourhi AU - Emmanuelle Durand AU - Emmanuel Vaillant AU - Philippe Froguel AU - Régine Chambrey AU - Peter S Aronson AU - Amélie Bonnefond AU - Dominique Eladari Y1 - 2022/11/01 UR - http://jmg.bmj.com/content/59/11/1035.abstract N2 - 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&gt;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. ER -