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Nephrol Dial Transplant (2003) 18: 512-516
© 2003 European Renal Association-European Dialysis and Transplant Association

Exclusion of mutations in FXYD2, CLDN16 and SLC12A3 in two families with primary renal Mg2+ loss

Iwan C. Meij1, Lambert P. W. J. van den Heuvel1, Sies Hemmes2, Walter A. van der Vliet1, Johannes L. Willems3, Leo A. H. Monnens1 and Nine V. A. M. Knoers4,

1 Department of Pediatrics, 3 Department of Clinical Chemistry and 4 Department of Human Genetics, University Hospital Nijmegen, Nijmegen and 2 Department of Pediatrics, Gelderse Vallei Ziekenhuis Ede, The Netherlands

Background. Based on genetic studies in families with hereditary renal Mg2+ reabsorption disorders, several genes were shown to be involved in renal Mg2+ transport. Mutations in the CLDN16 gene were found to underlie autosomal recessive hypomagnesaemia associated with hypercalciuria and nephrocalcinosis. The FXYD2 gene was implicated in autosomal dominant renal Mg2+ wasting associated with hypocalciuria. Mutations in the SLC12A3 gene, also known as NCC, cause Gitelman's syndrome. In addition to hypokalaemic metabolic alkalosis, hypomagnesaemia associated with hypocalciuria is considered to be a hallmark feature of this latter disorder.

Methods. We have characterized a new family with presumed dominant renal hypomagnesaemia by detailed clinical examination and mutation analysis of CLDN16, FXYD2 and SLC12A3. In addition, we have performed mutation analysis of these three genes in a previously described family with autosomal recessive renal Mg2+ wasting. In this family, linkage analysis was performed with polymorphic markers in the vicinity of the FXYD2 gene.

Results. The phenotype of the new family closely resembles that of the known dominant families with a mutation in FXYD2, but mutations in this gene were not identified in the new family. No mutations were found in CLDN16 and SLC12A3 either. Sequencing of the three genes in the patients of the recessive family revealed no mutations. In addition, haplotype analysis excluded linkage to the FXYD2 region on chromosome 11q23.

Conclusion. Our results indicate that, in addition to the currently known loci involved in renal Mg2+ handling, at least one other gene must be involved.

Keywords: CLDN16; FXYD2; hypomagnesaemia; magnesium; renal; SLC12A3

Correspondence and offprint requests to: N. V. A. M. Knoers, MD, PhD, Department of Human Genetics 417, University Medical Centre Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Email: n.knoers{at}antrg.azn.nl


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