Annotation: Hereditary tubulointerstitial kidney diseases (TKD) are characterized by slowly progressive chronic kidney disease with minimal proteinuria and bland urinary sediment. Long under-recognized because of nonspecific features and inconsistent terminology, TKDs nevertheless offer key insights into the pathophysiology of chronic kidney disease.

Following the identification of a single Czech family in 1996, we pursued a multidisciplinary approach that led to identification of TKD-causing genes, the creation of an international Rare Inherited Kidney Disease (RIKD) registry encompassing over 1,500 families, with genetic diagnoses established in more than 1,000. Most cases result from mutations in UMOD and MUC1 genes, together accounting for up to 25% of inherited kidney disease, particularly in adults aged ≥60 years.

We showed that these mutations disrupt protein biogenesis and trafficking, inducing endoplasmic reticulum stress and the unfolded protein response, thereby establishing TKDs as toxic proteinopathies. Building on this mechanistic insight, our work contributed to the discovery of the small molecule BRD4780 and to the investigation of gene-targeting and antisense oligonucleotide strategies aimed at reducing mutant protein burden. These approaches are currently being evaluated in preclinical mouse and rat models, advancing therapeutic development for TKDs and related toxic proteinopathies.

Biography: Stanislav Kmoch is a professor of Medical Biology and Genetics at the First Faculty of Medicine, Charles University in Prague. He leads the Research Unit for Rare Diseases within the Department of Pediatrics and Inherited Metabolic Disorders and co-founded the National Center for Medical Genomics. He is also Adjunct Professor of Nephrology at Wake Forest School of Medicine, USA, and a Visiting Scientist at the Broad Institute of MIT and Harvard. His research focuses on the genetic and molecular basis of rare inherited diseases and the role of rare variants in complex disorders.

IPHYS contact person: Jan Kopecký, M.D., D.Sc., Laboratory of Adipose Tissue Biology; jan.kopecky@fgu.cas.cz