Background: Based on genetic studies in families with hereditary renal Mg(2+) reabsorption disorders, several genes were shown to be involved in renal Mg(2+) 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 Mg(2+) 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 Mg(2+) 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 Mg(2+) handling, at least one other gene must be involved.