title: Predicted Mutation Strength of Nontruncating PKD1 Mutations Aids Genotype-Phenotype Correlations in Autosomal Dominant Polycystic Kidney Disease.
abstract: Autosomal dominant polycystic kidney disease (ADPKD) often results in ESRD but with a highly variable course. Mutations to PKD1 or PKD2 cause ADPKD; both loci have high levels of allelic heterogeneity. We evaluated genotype-phenotype correlations in 1119 patients (945 families) from the HALT Progression of PKD Study and the Consortium of Radiologic Imaging Study of PKD Study. The population was defined as: 77.7% PKD1, 14.7% PKD2, and 7.6% with no mutation detected (NMD). Phenotypic end points were sex, eGFR, height-adjusted total kidney volume (htTKV), and liver cyst volume. Analysis of the eGFR and htTKV measures showed that the PKD1 group had more severe disease than the PKD2 group, whereas the NMD group had a PKD2-like phenotype. In both the PKD1 and PKD2 populations, men had more severe renal disease, but women had larger liver cyst volumes. Compared with nontruncating PKD1 mutations, truncating PKD1 mutations associated with lower eGFR, but the mutation groups were not differentiated by htTKV. PKD1 nontruncating mutations were evaluated for conservation and chemical change and subdivided into strong (mutation strength group 2 [MSG2]) and weak (MSG3) mutation groups. Analysis of eGFR and htTKV measures showed that patients with MSG3 but not MSG2 mutations had significantly milder disease than patients with truncating cases (MSG1), an association especially evident in extreme decile populations. Overall, we have quantified the contribution of genic and PKD1 allelic effects and sex to the ADPKD phenotype. Intrafamilial correlation analysis showed that other factors shared by families influence htTKV, with these additional genetic/environmental factors significantly affecting the ADPKD phenotype.
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota;
authors.forename: Christina M
authors.initials: CM
authors.lastname: Heyer
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota;
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Sundsbak
authors.affiliation: Center for Research on Health Care, and.
authors.forename: Kaleab Z
authors.initials: KZ
authors.lastname: Abebe
authors.affiliation: Section of Nephrology, University of Chicago, Chicago, Illinois;
authors.forename: Arlene B
authors.initials: AB
authors.lastname: Chapman
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota;
authors.forename: Vicente E
authors.initials: VE
authors.lastname: Torres
authors.affiliation: Kidney Institute, Kansas University Medical Center, Kansas City, Kansas;
authors.forename: Jared J
authors.initials: JJ
authors.lastname: Grantham
authors.affiliation: Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;
authors.forename: Kyongtae T
authors.initials: KT
authors.lastname: Bae
authors.affiliation: Division of Nephrology, University of Colorado Health Sciences Center, Denver, Colorado;
authors.forename: Robert W
authors.initials: RW
authors.lastname: Schrier
authors.affiliation: Division of Nephrology, Tufts Medical Center, Boston, Massachusetts;
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Perrone
authors.affiliation: Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio;
authors.forename: William E
authors.initials: WE
authors.lastname: Braun
authors.affiliation: Division of Nephrology, Beth Israel Deaconess Medical Center, Boston, Massachusetts;
authors.forename: Theodore I
authors.initials: TI
authors.lastname: Steinman
authors.affiliation: Division of Nephrology, University of Alabama, Birmingham, Alabama;
authors.forename: Michal
authors.initials: M
authors.lastname: Mrug
authors.affiliation: Kidney Institute, Kansas University Medical Center, Kansas City, Kansas;
authors.forename: Alan S L
authors.initials: AS
authors.lastname: Yu
authors.affiliation: Division of Nephrology, University of Colorado Health Sciences Center, Denver, Colorado;
authors.forename: Godela
authors.initials: G
authors.lastname: Brosnahan
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota;
authors.forename: Katharina
authors.initials: K
authors.lastname: Hopp
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota;
authors.forename: Maria V
authors.initials: MV
authors.lastname: Irazabal
authors.affiliation: Legacy Transplant Services, Legacy Good Samaritan Hospital, Portland, Oregon;
authors.forename: William M
authors.initials: WM
authors.lastname: Bennett
authors.affiliation: National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland; and.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Flessner
authors.affiliation: Dickson Advanced Analytics, Carolinas HealthCare System, Charlotte, North Carolina.
authors.forename: Charity G
authors.initials: CG
authors.lastname: Moore
authors.affiliation: Center for Research on Health Care, and.
authors.forename: Douglas
authors.initials: D
authors.lastname: Landsittel
authors.affiliation: Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota; harris.peter@mayo.edu.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Harris
mesh_terms: D000328:Adult; D005260:Female; D005544:Forecasting; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics*; D050396:TRPP Cation Channels / Q000235:genetics*
chemical_list: D050396:TRPP Cation Channels
keywords: ADPKD; Genotype/phenotype; Prognostic studies
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