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
Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, New York.
Dipartimento di Medicina e Chirurgia, Università di Parma, Unità Operativa Nefrologia, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
J Am Soc Nephrol. 2025 Feb 1;36(2):274-289. doi: 10.1681/ASN.0000000501. Epub 2024 Oct 1.
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.
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 to help define the specific features of disease and further facilitate drug development and clinical trials design.
The study involved 64 individuals from 39 families with 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 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.
Large-scale sequencing data did not support causality for protein-truncating variants. We identified 21 unique 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.
This study provides insights into the genetic spectrum, clinicopathological associations, and natural history of TRPC6-AP.
: A Study to Test BI 764198 in People With a Type of Kidney Disease Called Focal Segmental Glomerulosclerosis, NCT05213624.
我们对来自39个家庭的64例与TRPC6相关的足细胞病（TRPC6-AP）患者进行了临床、基因和病理分析。对37542名个体的分析排除了功能丧失变异对TRPC6-AP的主要影响，为当前的药物研发方法提供了合理性依据。本研究确定了有助于干预研究设计的疾病关键特征，并提示了TRPC6-AP与原发性局灶节段性肾小球硬化（FSGS）之间的相似性。
了解人类疾病的遗传基础已成为药物开发和精准医学不可或缺的一部分。最近的进展使得能够识别驱动疾病的分子途径，从而产生靶向治疗策略。生物技术行业对罕见病的投资不断增加，凸显了遗传证据在药物研发和审批过程中的重要性。在此，我们研究了一种单基因孟德尔遗传性肾脏疾病——TRPC6相关足细胞病（TRPC6-AP），以呈现其在一大群具有致病变异的患者中的自然病史、遗传谱和临床病理关联，以帮助确定疾病的具体特征，并进一步促进药物开发和临床试验设计。
该研究纳入了来自39个家庭的64名携带致病错义变异的个体。从国内和国际多个中心收集了临床数据，包括发病年龄、实验室检查结果、治疗反应、肾活检结果和遗传信息。进行了外显子组或靶向测序，并根据严格标准对变异进行分类。对变异进行了结构和功能分析，以了解其对蛋白质功能的影响。对9份可用肾活检的光镜和电镜标本进行了深入重新分析，以确定TRPC6-AP的病理特征及其相关性。
大规模测序数据不支持蛋白质截短变异的因果关系。我们鉴定出21种独特的错义变异，聚集在蛋白质的三个不同区域，对TRPC6三维蛋白质结构有不同影响。肾活检分析显示，大多数病例呈现FSGS损伤模式，伴有独特的足细胞特征，包括弥漫性足突消失和细胞体肿胀。大多数患者在青春期或成年早期发病，但存在很大差异（平均22岁，标准差±14岁），经常进展为肾衰竭，但从发病到肾衰竭的时间存在差异。
本研究深入探讨了TRPC6-AP的遗传谱、临床病理关联和自然病史。
一项在患有局灶节段性肾小球硬化症的人群中测试BI 764198的研究，NCT05213624。
