Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive tubular disorder that is frequently associated with progressive renal failure. The primary defect is related to impaired tubul ar reabsorption of magnesium and calcium in the thick ascending limb of Hen le's loop. Mutations in PCLN-1, which encodes the renal tight junction prot ein paracellin-1 (claudin-16), were identified as the underlying genetic de fects. Comprehensive clinical data and the results of PCLN-1 mutation analy sis of 25 FHHNC families with 33 affected individuals are presented. Patien ts presented mainly with urinary tract infections, polyuria, and hematuria at a median age of 3.5 yr. At the time of diagnosis. the GFR was already de creased to <60 ml/min per 1.73 m(2) for 11 patients. Twelve patients exhibi ted progression to end-stage renal disease, at a median age of 14.5 yr. Tre atment with magnesium salts and thiazides seemed to have no effect on the p rogression of the disease. Genotype analysis revealed PCLN-1 mutations in a ll except three mutant alleles (94%). Fifteen different mutations were obse rved, including eight novel mutations. The accumulation of mutations affect ing the first extracellular loop was striking, with 48% of all mutant allel es exhibiting a Leul51Phe exchange. Haplotype analysis strongly suggested a founder effect among patients with FHHNC who originated from Germany or ea stern European countries. In 13 of 23 families, hypercalciuria and/or nephr olithiasis were observed in otherwise unaffected family members, indicating a possible role of heterozygous PCLN-1 mutations in yielding hypercalciuri c stone-forming conditions.