BACKGROUND/AIMS: Pseudohypoaldosteronism type I (PHAI) is an inherited disorder characterized by renal salt wasting, hyperkalemic metabolic acidosis, and hyperaldosteronism. Its known causes are mutations in the mineralocorticoid receptor and the epithelial sodium channel (ENaC), but there are reports of genetic heterogeneity. Claudin-8 is a tight junction protein that acts as a paracellular cation barrier in the distal nephron. The aim of this study was to test the hypothesis that mutations in claudin-8, which would be expected to induce a distal tubule cation leak, can be a cause of PHAI. METHODS: We identified 10 patients with autosomal dominant PHAI in whom mutations in the mineralocorticoid receptor and ENaC had been excluded. The claudin-8 gene and upstream region was sequenced in all patients. RESULTS: No disease-associated claudin-8 mutations were identified. A novel polymorphic allele in the 3'-untranslated region was identified in 2 patients, but was also found in 15% of individuals in a panel of normal controls. CONCLUSION: We present further evidence for locus heterogeneity in PHAI. Mutations in claudin-8 are unlikely to be a cause of PHAI. Further studies of other claudins in this disease are warranted. 2004 S. Karger AG, Basel
BACKGROUND/AIMS: Pseudohypoaldosteronism type I (PHAI) is an inherited disorder characterized by renal salt wasting, hyperkalemic metabolic acidosis, and hyperaldosteronism. Its known causes are mutations in the mineralocorticoid receptor and the epithelial sodium channel (ENaC), but there are reports of genetic heterogeneity. Claudin-8 is a tight junction protein that acts as a paracellular cation barrier in the distal nephron. The aim of this study was to test the hypothesis that mutations in claudin-8, which would be expected to induce a distal tubule cation leak, can be a cause of PHAI. METHODS: We identified 10 patients with autosomal dominant PHAI in whom mutations in the mineralocorticoid receptor and ENaC had been excluded. The claudin-8 gene and upstream region was sequenced in all patients. RESULTS: No disease-associated claudin-8 mutations were identified. A novel polymorphic allele in the 3'-untranslated region was identified in 2 patients, but was also found in 15% of individuals in a panel of normal controls. CONCLUSION: We present further evidence for locus heterogeneity in PHAI. Mutations in claudin-8 are unlikely to be a cause of PHAI. Further studies of other claudins in this disease are warranted. 2004 S. Karger AG, Basel