Novel Paracellin-1 Mutations in 25 Families with Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis

Abstract

Abstract. 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 tubular reabsorption of magnesium and calcium in the thick ascending limb of Henle's loop. Mutations inPCLN-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 ofPCLN-1mutation 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 m2for 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 revealedPCLN-1mutations 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 Leu151Phe 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 heterozygousPCLN-1mutations in yielding hypercalciuric stone-forming conditions.

Hereditary kidney diseases associated with hypomagnesemia

“…Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive tubular disorder characterized by excessive urinary loss of Mg 2+ and Ca 2+ , bilateral nephrocalcinosis, and progressive chronic kidney disease (CKD) [17]. FHHNC patients typically present during early childhood or before adolescence with recurrent urinary tract infections, polyuria, polydipsia, nephrolithiasis, and failure to thrive [18][19][20][21]. FHHNC patients may show a pronounced decline in glomerular filtration rate at the time of diagnosis, and approximately one-third of cases progress to chronic renal failure during childhood or adolescence [21,22].…”

“…parathyroid hormone (PTH) before the onset of chronic renal failure [1,19,23]. In some cases, patients present amelogenesis imperfecta [24,25].…”

“…FHHNC patients may show a pronounced decline in glomerular filtration rate at the time of diagnosis, and approximately one-third of cases progress to chronic renal failure during childhood or adolescence [ 21 , 22 ]. In contrast to patients with other hypomagnesemias, FHHNC patients have high serum levels of parathyroid hormone (PTH) before the onset of chronic renal failure [ 1 , 19 , 23 ]. In some cases, patients present amelogenesis imperfecta [ 24 , 25 ].…”

Correction: Claudin-19 Mutations and Clinical Phenotype in Spanish Patients with Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis

“…Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC; MIM #248250) is an autosomal recessive tubular disease characterized by renal magnesium and calcium wasting [1]. FHHNC patients usually present during early childhood or before adolescence with recurrent urinary tract infections, polyuria/polydipsia, nephrolithiasis, and/or failure to thrive [2][3][4]. Complications of hypomagnesemia such as seizures and muscular tetany are less common.…”

“…Konrad and colleagues reported nine families affected with FHHNC that did not have any mutations in CLDN16 [15]. These families were distinct in that affected individuals showed severe ocular defects including severe myopia, nystagmus, and macular colobomata, features that are not present or appear mildly among patients with CLDN16 mutations [3,15]. Another tight junction gene, CLDN19, was identified as the cause of the disease in these patients [15].…”