title: Novel PKD1 and PKD2 mutations in Taiwanese patients with autosomal dominant polycystic kidney disease.
abstract: Autosomal dominant polycystic kidney disease (ADPKD) is a heterogeneous disease caused by mutations in PKD1 and PKD2. The genotype-phenotype correlations are not completely understood. We performed direct PCR-sequencing plus multiplex ligation-dependent probe amplification for PKD1 and PKD2 in 46 unrelated patients. Disease-causing mutations were identified in 30 (65%) patients: 23 (77%) patients have mutations in PKD1 and 7 (23%) have mutations in PKD2. Nonsense, splicing or frame-shifting mutations were found in 18 patients, exon duplication in 1 and missense mutations in 11 patients. Two likely PKD1 hypomorphic alleles (p.Arg2477His and p.Arg3439Trp) segregated with mild disease in a family. A total of 34 mutations were identified and 17 (50%) of which are novel. The median age at onset of dialysis was significantly earlier in patients with PKD1 mutations (52 years) than in patients with PKD2 mutations (65.5 years) and those with an undetermined genotype (67 years) by survival analysis (log-rank test, P=0.014). Patients carrying PKD1-truncating mutations have a trend toward earlier initiation of dialysis compared with carriers of non-truncating mutations (52 years vs 57 years, P=0.061). A family history of dialysis before 55 years was more common in PKD1 patients than in others (P<0.05). In conclusion, this study identified novel mutations in PKD1 and PKD2 and demonstrated the presence of PKD1 hypomorphic alleles in Taiwanese patients. Patients carrying PKD1 mutations, especially those with truncating mutations, could have a more rapidly progressive disease than others. These results might have implications for diagnosis and risk stratification in patients with ADPKD.
authors.affiliation: Kidney Research Center and Department of Nephrology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.
authors.forename: Ming-Yang
authors.initials: MY
authors.lastname: Chang
authors.forename: Hsiao-Mang
authors.initials: HM
authors.lastname: Chen
authors.forename: Chang-Chyi
authors.initials: CC
authors.lastname: Jenq
authors.forename: Shen-Yang
authors.initials: SY
authors.lastname: Lee
authors.forename: Yu-Ming
authors.initials: YM
authors.lastname: Chen
authors.forename: Ya-Chung
authors.initials: YC
authors.lastname: Tian
authors.forename: Yung-Chang
authors.initials: YC
authors.lastname: Chen
authors.forename: Cheng-Chieh
authors.initials: CC
authors.lastname: Hung
authors.forename: Ji-Tseng
authors.initials: JT
authors.lastname: Fang
authors.forename: Chih-Wei
authors.initials: CW
authors.lastname: Yang
authors.forename: Yah-Huei
authors.initials: YH
authors.lastname: Wu-Chou
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics*; D016415:Sequence Alignment; D050396:TRPP Cation Channels / Q000235:genetics*; D013624:Taiwan
chemical_list: D050396:TRPP Cation Channels