| Title: | Dominant negative mutation in oxalate transporter SLC26A6 associated with enteric hyperoxaluria and nephrolithiasis |
| Journal: | Journal of Medical Genetics |
| Published: | 3 Feb 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/35115415/ |
| DOI: | https://doi.org/10.1136/jmedgenet-2021-108256 |
| URL: | https://jmg.bmj.com/content/jmedgenet/early/2022/02/03/jmedgenet-2021-108256.full.pdf |
Publication 13864
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
Abstract
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.</p>
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.</p>
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.</p>
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.</p>
9 Keywords
- Antiporters
- Calcium
- Calcium Oxalate
- Humans
- Hyperoxaluria
- Mutation
- Nephrolithiasis
- Oxalates
- Sulfate Transporters
18 Authors
- Nicolas Cornière
- R Brent Thomson
- Stéphanie Thauvin
- Bruno O Villoutreix
- Sophie Karp
- Diane W Dynia
- Sarah Burlein
- Lennart Brinkmann
- Alaa Badreddine
- Aurélie Dechaume
- Mehdi Derhourhi
- Emmanuelle Durand
- Emmanuel Vaillant
- Philippe Froguel
- Régine Chambrey
- Peter S Aronson
- Amélie Bonnefond
- Dominique Eladari
1 Application
| Application ID | Title |
|---|---|
| 67575 | Contribution of rare DNA variants to the risk of metabolic disorders and to the level of associated metabolic traits |
Enabling scientific discoveries that improve human health