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

Autor:	Cornière N; Department of Precision Médicine for Metabolic and Renal Diseases, CHU Amiens Picardie, Université de Picardie Jules Verne, Amiens, France.; UMR1283, INSERM; CNRS; University of Lille, Lille, Hauts de France, France., Thomson RB; Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA., Thauvin S; Plateau de Recherche ODHIR, AURAR, Saint-Gilles-les-Bains, Réunion., Villoutreix BO; UMR 1141, INSERM, Paris, Île-de-France, France., Karp S; Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA., Dynia DW; Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA., Burlein S; Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA., Brinkmann L; Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA., Badreddine A; UMR1283, INSERM; CNRS; University of Lille, Lille, Hauts de France, France., Dechaume A; UMR1283, INSERM; CNRS; University of Lille, Lille, Hauts de France, France., Derhourhi M; UMR1283, INSERM; CNRS; University of Lille, Lille, Hauts de France, France., Durand E; UMR1283, INSERM; CNRS; University of Lille, Lille, Hauts de France, France., Vaillant E; UMR1283, INSERM; CNRS; University of Lille, Lille, Hauts de France, France., Froguel P; UMR1283, INSERM; CNRS; University of Lille, Lille, Hauts de France, France., Chambrey R; UMR1283, INSERM; CNRS; University of Lille, Lille, Hauts de France, France.; Plateau de Recherche ODHIR, AURAR, Saint-Gilles-les-Bains, Réunion., Aronson PS; Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA., Bonnefond A; UMR1283, INSERM; CNRS; University of Lille, Lille, Hauts de France, France., Eladari D; Department of Precision Médicine for Metabolic and Renal Diseases, CHU Amiens Picardie, Université de Picardie Jules Verne, Amiens, France dominique.eladari@inserm.fr.; UMR1283, INSERM; CNRS; University of Lille, Lille, Hauts de France, France.
Jazyk:	angličtina
Zdroj:	Journal of medical genetics [J Med Genet] 2022 Nov; Vol. 59 (11), pp. 1035-1043. Date of Electronic Publication: 2022 Feb 03.
DOI:	10.1136/jmedgenet-2021-108256
Abstrakt:	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. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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