Background FHHNC is a rare autosomal recessive tubulopathy of the thick ascending limb due to inactivating mutations in the Claudin-16 and Claudin-19 genes which are responsible for the paracellular reabsorption of calcium and magnesium. Clinically, FHHNC is characterized by urinary tract infections, nephrolithiasis, nephrocalcinosis and progressive renal failure.
Objective To present clinical and molecular data on 2 siblings with FHHNC and early onset SND, found to have a new mutation in the Claudin-16 gene.
Methods A 16-year-old male and his 14-year-old sister were diagnosed with chronic kidney disease since early infancy, manifested by recurrent UTIs, polyuria and polydipsia, poor growth, mild mental retardation and delayed speech. SND was diagnosed at the age of 6 and 7 years. Both have hypomagnesemia, hypermagnesuria, hypercalciuria and nephrocalcinosis. Genotyping was performed by PCR using tetranucleotide repeat polymorphisms. Specific primer pairs of genomic DNA were used as template for sequencing the Cldin16 gene.
Results Exons 1, 2, 4 and 5 were amplified and revealed wild type sequencing but exon 3 failed in amplification by PCR. Long range PCR spanning exon 2 to 4 of the gene yielded a 2.5 kb fragment shared by the patients. Sequencing of this fragment reveal a 2630 bp deletion including the entire exon 3 resulting in deletion and frame shift of Cldn16 protein.
Conclusion This family demonstrates the first identified homozygous mutation in the Cldn16 gene causing the deletion of an entire exon. This, however, is unlikely to explain the SND, since this gene is not expressed in the cochlea.