Kidney Week

Abstract: SA-PO576

Comparative PKD1 and PKD2 Missense Variant Profiling Aids Molecular Diagnoses and Reveals Common Pathomechanisms and Variant Subtypes across the ADPKD Spectrum

Session Information

• Cystic Kidney Diseases: Genetic Causes, Modifiers, and Extrarenal Manifestations
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic

Authors

• Sieben, Cynthia J., Mayo Clinic Research Rochester, Rochester, Minnesota, United States

Cynthia J. Sieben, PhD

• Gainullin, Vladimir G., Mayo Clinic Research Rochester, Rochester, Minnesota, United States

Vladimir G. Gainullin, PhD

• Heyer, Christina M., Mayo Clinic Research Rochester, Rochester, Minnesota, United States

Christina M. Heyer

• Elbarougy, Doaa E., Mayo Clinic Research Rochester, Rochester, Minnesota, United States

Doaa E. Elbarougy, MBChB

• Senum, Sarah R., Mayo Clinic Research Rochester, Rochester, Minnesota, United States

Sarah R. Senum, MS

• Wang, Zhifei, St. John's University, Queens, New York, United States

Zhifei Wang, PhD

• Sun, Xiaobo, Mayo Clinic Research Rochester, Rochester, Minnesota, United States

Xiaobo Sun

• Yang, Hana, Mayo Clinic Research Rochester, Rochester, Minnesota, United States

Hana Yang, PhD

• Sturmlechner, Ines, Mayo Clinic Research Rochester, Rochester, Minnesota, United States

Ines Sturmlechner, PhD

• Yu, Yong, St. John's University, Queens, New York, United States

Yong Yu, PhD

• Harris, Peter C., Mayo Clinic Research Rochester, Rochester, Minnesota, United States

Peter C. Harris, PhD

Background

ADPKD is characterized by the formation and growth of fluid-filled renal cysts, often leading to kidney failure (KF). Typically, monoallelic PKD1 or PKD2 (encoding PC1 and PC2) variants cause ADPKD, however, complex inheritance and a broad phenotypic spectrum exist. The advent of genomewide variant screening emphasizes the importance of ADPKD molecular diagnostic methods to reliably determine the pathogenicity of variants of uncertain significance (VUS).

Methods

Here, we evaluated the pathogenicity/penetrance of 48 PKD1 and 44 PKD2 missense variants using in silico (ACMG guidelines [clinical] and Variant Strength Group [VSG; research] categorization) and in vitro (PC1 maturation/trafficking to the cell surface [sPC1; requires PC1/2 complex formation] using a cell-based flow cytometry assay, and PC1/2 channel activity employing Xenopus oocytes) methods. The in vitro results were correlated with in silico predictions and patient phenotypes (htTKV, eGFR, and KF), including employing the population-based, Mayo Clinic Biobank (MCBB).

Results

The majority of proposed monoallelic PKD1 and PKD2 variants assayed close to fully penetrant (~68%, <20% sPC1), whereas biallelic and digenic PKD1 and PKD2 variants ranged from strong hypomorphs (25% biallelic PKD1; 20-40% sPC1) to mild or benign (75% biallelic PKD1, 100% biallelic/digenic PKD2; 50-110% sPC1). Most were associated with aberrant folding (~85% PKD1, 68% PKD2). Analysis of Ca²⁺ channel activity for mild/benign sPC1 variants (12 PKD1 and 14 PKD2, monoallelic and complex), occasionally suggested channel defects (~8% PKD1, 14% PKD2). Variant sPC1 levels showed correlations with clinical endpoints (htTKV, eGFR, and KF). Analyses of two hypomorphic variants (PKD1 p.Arg3277Cys and p.Ile3167Phe) in the MCBB, revealed correlations between sPC1 levels (~27 and 64%) and disease penetrance (~20 and 5% with ICD cystic codes).

Conclusion

Together, these studies reveal: 1) the value of combining in silico, functional, and population data for PKD1 and PKD2 variant evaluation, 2) aberrant PC1 trafficking as a common PKD1/2-mediated pathomechanism and disease determinant, and 3) enhanced PC1/2 folding as a potential therapy in ADPKD.

Funding

• NIDDK Support