Author/Editor		Weber, Stefanie; Schneider, Linda; Peters, Melanie; Misselwitz, Joachim; Roennefarth, Gabriele; Boeswald, Michael; Bonzel, Kluas E; Seeman, Tomas; Sulakova, Tereza; Gregorič, Alojz
Title		Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciurua and nephrocalcinosis
Type		članek
Source		J Am Soc Nephrol
Vol. and No.		Letnik 12, št. 9
Publication year		2001
Volume		str. 1872-81
Language		eng
Abstract		Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recesive tubular disorder that is frequently associated with progressive renal failure. The primary defect is related to impaired tubular reabsorption of magnesium and calcium in the thick ascending limb of Henles loop. Mutations in PCLN-1, which encodes the renal tight junction protein paracellin-1 (claudin-16), were identified as the underlying genetic defects. Comprehensive clinical data and the results of PCLN-1 mutation analysis of 25 FHHNC families with 33 affected individuals are presented. Patients 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 decreased to <60 ml/min per 1.73 m2 for 11 patients. Twelve patients exhibited progression to end-stage renal disease, at a median age of 14.5 yr. Treatment with magnesium salts and thiazides seemed to have no effect on the progression of the disease. Genotype analysis revealed PCLN-1 mutations in all except three mutant alleles (94%). Fifteen different mutations were observed, including eight novel mutations. The accumulation of mutations affecting the first extracellular loop was striking, with 48% of all mutant alleles exhibiting a Leu 151 Phe exchange. Haplotype analysis strongly suggested a founder effect among patients with FHHNC who originated from Germany or eastern European countries. In 13 of 23 families, hypercalciuria and/or nephrolithiasis were observed in otherwise unaffected family members, indicating a possible role of heterozygous PCLN-1 mutations in yielding hypercalciuric stone-forming conditions.
Descriptors		MAGNESIUM CALCIUM NEPHROCALCINOSIS GLOMERULAR FILTRATION RATE MUTATION HAPLOTYPES PEDIGREE ALLELES