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Transcriptional and Functional Analyses of SLC12A3 Mutations: New Clues for the Pathogenesis of Gitelman Syndrome

Eva Riveira-Munoz^*, Qing Chang, Nathalie Godefroid^*, Joost G. Hoenderop, René J. Bindels, Karin Dahan, Olivier Devuyst^* for the Belgian Network for the Study of Gitelman Syndrome

^* Division of Nephrology; Department of Human Genetics, Université Catholique de Louvain Medical School, Brussels, Belgium; and Department of Physiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

Address correspondence to: Dr. Olivier Devuyst, Division of Nephrology, UCL Medical School, 10 Avenue Hippocrate, B-1200 Brussels, Belgium. Phone: +32-2-7641855; Fax: +32-2-7645455; Devuyst{at}nefr.ucl.ac.be

Received for publication October 7, 2006. Accepted for publication January 9, 2007.

Gitelman syndrome (GS) is a recessive salt-losing tubulopathy that is caused by mutations in the SLC12A3 gene that encodes the sodium-chloride co-transporter (NCC). GS is characterized by significant inter- and intrafamilial phenotype variability, with early onset and/or severe clinical manifestations in some patients. No correlations between the disease variability and the position/nature of SLC12A3 mutations have been investigated thus far. In this study, extensive mutational analyses of SLC12A3 were performed in 27 patients with GS, including genomic DNA sequencing, multiplex ligation-dependent probe amplification, cDNA analysis, and quantification of allele-specific transcripts, in parallel with functional analyses in Xenopus laevis oocytes and detailed phenotyping. Twenty-six SLC12A3 mutations were identified in 25 patients with GS, including eight novel (detection rate 80%). Transcript analysis demonstrated that splicing mutations of SLC12A3 lead to frameshifted mRNA subject to degradation by nonsense-mediated decay. Heterologous expression documented a novel class of NCC mutants with defective intrinsic transport activity. A subgroup of patients presented with early onset, growth retardation, and/or detrimental manifestations, confirming the potential severity of GS. The mutations that were associated with a severe presentation were the combination at least for one allele of a missplicing resulting in a truncated transcript that was downregulated by nonsense-mediated decay or a nonfunctional, cell surface–absent mutant. The most recurrent mutation on the second allele was a newly described NCC mutant that affected the functional properties of the co-transporter. These data suggest that the nature/position of SLC12A3 mutation, combined with male gender, is a determinant factor in the severity of GS and provide new insights in the underlying pathogenic mechanisms of the disease.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673