Natural History and Clinicopathological Associations of TRPC6-Associated Podocytopathy
Authors: Wooden Benjamin , Beenken Andrew , Martinelli Elena , Saida Ken , Knob Andrea L. , Ke Juntao , Pisani Isabella , Jin Gina , Lane Brandon , Mitrotti Adele , Colby Elizabeth , Lim Tze Y. , Guglielmi Francesca , Osborne Amy J. , Ahram Dina F. , Wang Chen , Armand Farid , Zanoni Francesca , Bomback Andrew S. , Delsante Marco , Appel Gerald B. , Ferrari Massimo R.A. , Martino Jeremiah , Sahdeo Sunil , Breckenridge David , Petrovski Slavé , Paul Dirk S. , Hall Gentzon , Magistroni Riccardo , Murtas Corrado , Feriozzi Sandro , Rampino Teresa , Esposito Pasquale , Helmuth Margaret E. , Sampson Matthew G. , Kretzler Matthias , Kiryluk Krzysztof , Shril Shirlee , Gesualdo Loreto , Maggiore Umberto , Fiaccadori Enrico , Gbadegesin Rasheed , Santoriello Dominick , D'Agati Vivette D. , Saleem Moin A. , Gharavi Ali G. , Hildebrandt Friedhelm , Pollak Martin R. , Goldstein David B. , Sanna-Cherchi Simone 
Published: October 2024

Key Points

We conducted a clinical, genetic, and pathological analysis on 64 cases from 39 families with TRPC6-associated podocytopathy (TRPC6-AP).

Analysis of 37,542 individuals excluded a major contribution of loss-of-function variants to TRPC6-AP, legitimating current drug discovery approaches.

This study identifies key features of disease that can help intervention studies design and suggests similarities between TRPC6-AP and primary FSGS.

Background

Understanding the genetic basis of human diseases has become integral to drug development and precision medicine. Recent advancements have enabled the identification of molecular pathways driving diseases, leading to targeted treatment strategies. The increasing investment in rare diseases by the biotech industry underscores the importance of genetic evidence in drug discovery and approval processes. Here we studied a monogenic Mendelian kidney disease, TRPC6-associated podocytopathy (TRPC6-AP), to present its natural history, genetic spectrum, and clinicopathological associations in a large cohort of patients with causal variants in TRPC6 to help define the specific features of disease and further facilitate drug development and clinical trials design.

Methods

The study involved 64 individuals from 39 families with TRPC6 causal missense variants. Clinical data, including age of onset, laboratory results, response to treatment, kidney biopsy findings, and genetic information, were collected from multiple centers nationally and internationally. Exome or targeted sequencing was performed, and variant classification was based on strict criteria. Structural and functional analyses of TRPC6 variants were conducted to understand their effect on protein function. In-depth reanalysis of light and electron microscopy specimens for nine available kidney biopsies was conducted to identify pathological features and correlates of TRPC6-AP.

Results

Large-scale sequencing data did not support causality for TRPC6 protein-truncating variants. We identified 21 unique TRPC6 missense variants, clustering in three distinct regions of the protein, and with different effects on TRPC6 3D protein structure. Kidney biopsy analysis revealed FSGS patterns of injury in most cases, along with distinctive podocyte features including diffuse foot process effacement and swollen cell bodies. Most patients presented in adolescence or early adulthood but with ample variation (average 22, SD ±14 years), with frequent progression to kidney failure but with variability in time between presentation and kidney failure.

Conclusions

This study provides insights into the genetic spectrum, clinicopathological associations, and natural history of TRPC6-AP.

Clinical Trial registry name and registration number:

A Study to Test BI 764198 in People With a Type of Kidney Disease Called Focal Segmental Glomerulosclerosis, NCT05213624.