title: Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis.
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 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 m(2) 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 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 heterozygous PCLN-1 mutations in yielding hypercalciuric stone-forming conditions.
authors.affiliation: Department of Pediatrics, Philipps University, Marburg, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Weber
authors.affiliation: Department of Pediatrics, Philipps University, Marburg, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Schneider
authors.affiliation: Department of Pediatrics, Philipps University, Marburg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Peters
authors.affiliation: Department of Pediatrics, University Hospital, Jena, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Misselwitz
authors.affiliation: Department of Pediatrics, University Hospital, Jena, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Rönnefarth
authors.affiliation: Department of Pediatrics, University Hospital, Erlangen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Böswald
authors.affiliation: Department of Pediatrics, University Hospital, Essen, Germany.
authors.forename: Klaus E
authors.initials: KE
authors.lastname: Bonzel
authors.affiliation: Department of Pediatrics, University Hospital, Prague, Czech Republic.
authors.forename: Tomas
authors.initials: T
authors.lastname: Seeman
authors.affiliation: Department of Pediatrics, University Hospital, Ostrava, Czech Republic.
authors.forename: Tereza
authors.initials: T
authors.lastname: Suláková
authors.affiliation: Department of Pediatrics, University Hospital, Münster, Germany.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Kuwertz-Bröking
authors.affiliation: Department of Pediatrics, University Hospital, Maribor, Slovenia.
authors.forename: Alojz
authors.initials: A
authors.lastname: Gregoric
authors.affiliation: Department of Pediatrics, University Hospital, Clermont-Ferrand, France.
authors.forename: Jean-Bernard
authors.initials: JB
authors.lastname: Palcoux
authors.affiliation: Clinic for Children's Diseases, Skopje, Macedonia.
authors.forename: Velibor
authors.initials: V
authors.lastname: Tasic
authors.affiliation: Research Institute of Child Nutrition, Dortmund, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Manz
authors.affiliation: Department of Pediatrics, University Hospital, Heidelberg, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Schärer
authors.affiliation: Department of Pediatrics, Philipps University, Marburg, Germany.
authors.forename: Hannsjörg W
authors.initials: HW
authors.lastname: Seyberth
authors.affiliation: Department of Pediatrics, Philipps University, Marburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Konrad
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence / Q000235:genetics; D002118:Calcium / Q000652:urine*; D002648:Child; D002675:Child, Preschool; D057167:Claudins; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007668:Kidney / Q000503:physiopathology; D008274:Magnesium / Q000097:blood*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009397:Nephrocalcinosis / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D010375:Pedigree; D010641:Phenotype
chemical_list: D057167:Claudins; D008565:Membrane Proteins; C502010:claudin 16; D008274:Magnesium; D002118:Calcium