Natural History and Clinicopathological Associations of TRPC6-Associated Podocytopathy

作者：Benjamin Wooden, Andrew Beenken, Elena Martinelli, Ken Saida, Andrea L. Knob, Juntao Ke, Isabella Pisani, Gina Jin, Brandon M. Lane, Adele Mitrotti, Elizabeth Colby, Tze Yin Lim, Francesca Guglielmi, Amy J. Osborne, Dina Ahram, Chen Wang, Farid Arman, Francesca Zanoni, Andrew S. Bomback, Marco Delsante, Gerald B. Appel, Massimo R.A. Ferrari, Jeremiah Martino, Sunil Sahdeo, David G. Breckenridge, Slavé Petrovski, Dirk S. Paul, Gentzon Hall, Riccardo Magistroni, Corrado Murtas, Sandro Feriozzi, Teresa Rampino, Pasquale Esposito, Margaret Helmuth, Matthew G. Sampson, Matthias Kretzler, Krzysztof Kiryluk, Shirlee Shril, Loreto Gesualdo, Umberto Maggiore, Enrico Fiaccadori, Rasheed Gbadegesin, Dominick Santoriello, Vivette D. D’Agati, Moin A. Saleem, Ali G. Gharavi, Friedhelm Hildebrandt, Martin R. Pollak, David B. Goldstein, Simone Sanna‐Cherchi · 发表于：Journal of the American Society of Nephrology · 年份：2024 · DOI：10.1681/asn.0000000501 · 被引用次数：18 · 研究领域：Renal Diseases and Glomerulopathies

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 an...