Steroid resistant nephrotic syndrome (SRNS) – Discover and functionally characterize full-penetrance causes of SRNS

• Applicant: Dr. Katharina Lemberg
• Subject Area: Human Genetics ; General Genetics and Functional Genome Biology ; Nephrology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 461126211

The first objective is to discover the missing single-gene causes of Steroid resistant nephrotic syndrome (SRNS) by Whole Exome Sequencing in ~1,000 SRNS families.Rare recessive diseases offer powerful inroads into pathomechanisms, as they are caused by 'fullpenetrance alleles'. Healthy individuals carry ~5-10 different deleterious recessive disease alleles heterozygously. If mutated, recessive alleles segregate from each parent to a child, where they inescapably cause disease in the offspring. Identification of single-gene causes of SRNS has revolutionized the understanding of its pathogenesis. Whereas there are ~6,000 diseases with a suspected Mendelian basis, in ~3,000 the molecular basis is still unknown.The second objective is to functionally characterize newly identified single-gene causes of SRNS to delineate the pathogenesis and study ‘personalized’ genotype-phenotype and genotype-treatment correlations.The hypothesis underlying this research goal is that the discovery of novel SRNS genes will help elucidate novel insights into physiologic and pathogenic pathways relevant to nephrotic syndrome, when performing functional studies, using established CRISPR technology to the ‘podocyte migration assay’, mouse and zebrafish models of SRNS.Of the over 50 known monogenic causes of SRNS 42 involve recessive gene. Recessive mutations convey loss of function with full penetrance in childhood. Thus, they directly represent the cause of disease (etiology). In this way the gene products (proteins) of recessive disease genes are necessary cellular components to assure proper podocyte function, thereby making studies of subcellular localization and protein interaction partners central to the elucidation of disease mechanisms. It is very likely that further gene identification will delineate novel pathways, as recent gene identification has already done so. E.g. this pertains to 2 proteins involved in Coenzyme Q10 biosynthesis, 3 nuclear pore proteins and 4 proteins of the KEOPS complex.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Friedhelm Hildebrandt