title: Co-inheritance of a PKD1 mutation and homozygous PKD2 variant: a potential modifier in autosomal dominant polycystic kidney disease.
abstract: BACKGROUND
  Autosomal dominant polycystic kidney disease (ADPKD), which is caused by mutations in polycystins 1 (PC1) and 2 (PC2), is one of the most commonly inherited renal diseases, affecting ~1 : 1000 Caucasians.
  
  
  METHODS
  We screened Greek ADPKD patients with the denaturing gradient gel electrophoresis (DGGE) assay and direct sequencing.
  
  
  RESULTS
  We identified a patient homozygous for a nucleotide change c.1445T > G, resulting in a novel homozygous substitution of the non-polar hydrophobic phenylalanine to the polar hydrophilic cysteine in exon 6 at codon 482 (p.F482C) of the PKD2 gene and a de-novo PKD1 splice-site variant IVS21-2delAG. We did not find this PKD2 variant in a screen of 280 chromosomes of healthy subjects, supporting its pathogenicity. The proband's parents did not have the PKD1 mutation. Real-time PCR of the PKD2 transcript from a skin biopsy revealed 20-fold higher expression in the patient than in a healthy subject and was higher in the patient's peripheral blood mononuclear cells (PBMCs) than in those of her heterozygote daughter and a healthy subject. The greater gene expression was also supported by Western blotting. Inner medullar collecting duct (IMCD) cells transfected with the mutant PKD2 mouse gene presented a perinuclear and diffuse cytoplasmic localization compared with the wild type ER localization. Patch-clamping of PBMCs from the p.F482C homozygous and heterozygous subjects revealed lower polycystin-2 channel function than in controls.
  
  
  CONCLUSIONS
  We report for the first time a patient with ADPKD who is heterozygous for a de novo PKD1 variant and homozygous for a novel PKD2 mutation.
authors.affiliation: Department of Science Dietetics-Nutrition, Harokopio University of Athens, Athens, Greece. dedousi@hua.gr
authors.forename: G V Z
authors.initials: GV
authors.lastname: Dedoussis
authors.forename: Y
authors.initials: Y
authors.lastname: Luo
authors.forename: P
authors.initials: P
authors.lastname: Starremans
authors.forename: S
authors.initials: S
authors.lastname: Rossetti
authors.forename: A J
authors.initials: AJ
authors.lastname: Ramos
authors.forename: H F
authors.initials: HF
authors.lastname: Cantiello
authors.forename: E
authors.initials: E
authors.lastname: Katsareli
authors.forename: P
authors.initials: P
authors.lastname: Ziroyannis
authors.forename: K
authors.initials: K
authors.lastname: Lamnissou
authors.forename: P C
authors.initials: PC
authors.lastname: Harris
authors.forename: J
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D004586:Electrophoresis / Q000379:methods; D005260:Female; D006720:Homozygote; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000235:genetics*; D050396:TRPP Cation Channels
chemical_list: D011506:Proteins; D050396:TRPP Cation Channels