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 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.
Weber
Stefanie
S
Department of Pediatrics, Philipps University, Marburg, Germany.
Schneider
Linda
L
Department of Pediatrics, Philipps University, Marburg, Germany.
Peters
Melanie
M
Department of Pediatrics, Philipps University, Marburg, Germany.
Misselwitz
Joachim
J
Department of Pediatrics, University Hospital, Jena, Germany.
Rönnefarth
Gabriele
G
Department of Pediatrics, University Hospital, Jena, Germany.
Böswald
Michael
M
Department of Pediatrics, University Hospital, Erlangen, Germany.
Bonzel
Klaus E
KE
Department of Pediatrics, University Hospital, Essen, Germany.
Seeman
Tomas
T
Department of Pediatrics, University Hospital, Prague, Czech Republic.
Suláková
Tereza
T
Department of Pediatrics, University Hospital, Ostrava, Czech Republic.
Kuwertz-Bröking
Eberhard
E
Department of Pediatrics, University Hospital, Münster, Germany.
Gregoric
Alojz
A
Department of Pediatrics, University Hospital, Maribor, Slovenia.
Palcoux
Jean-Bernard
JB
Department of Pediatrics, University Hospital, Clermont-Ferrand, France.
Tasic
Velibor
V
Clinic for Children's Diseases, Skopje, Macedonia.
Manz
Friedrich
F
Research Institute of Child Nutrition, Dortmund, Germany.
Schärer
Karl
K
Department of Pediatrics, University Hospital, Heidelberg, Germany.
Seyberth
Hannsjörg W
HW
Department of Pediatrics, Philipps University, Marburg, Germany.
Konrad
Martin
M
Department of Pediatrics, Philipps University, Marburg, Germany.
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
D057167:Claudins; D008565:Membrane Proteins; C502010:claudin 16; D008274:Magnesium; D002118:Calcium