Basement membranes (BMs) are ubiquitous extracellular matrices whose composition remains elusive, limiting our understanding of BM regulation and function. By developing a bioinformatic and in vivo discovery pipeline, we define a network of 222 human proteins and their animal orthologs localized to BMs. Network analysis and screening in C. elegans and zebrafish uncovered BM regulators, including ADAMTS, ROBO, and TGFβ. More than 100 BM network genes associate with human phenotypes, and by screening 63,039 genomes from families with rare disorders, we found loss-of-function variants in LAMA5 , MPZL2 , and MATN2 and show that they regulate BM composition and function. This cross-disciplinary study establishes the immense complexity of BMs and their impact on in human health.

The glomerular filtration barrier is a highly specialized capillary wall comprising fenestrated endothelial cells, podocytes, and an intervening basement membrane. In glomerular disease, this barrier loses functional integrity, allowing the passage of macromolecules and cells, and there are associated changes in both cell morphology and the extracellular matrix. Over the past three decades there has been a transformation in our understanding about glomerular disease, fueled by genetic discovery, and this is leading to exciting advances in our knowledge about glomerular biology and pathophysiology. In current clinical practice, a genetic diagnosis already has important implications for management ranging from estimating the risk of disease recurrence post-transplant to the lifechanging advances in the treatment of atypical hemolytic uremic syndrome. Improving our understanding about the mechanistic basis of glomerular disease is required for more effective and personalized therapy options. In this review we describe genotype and phenotype correlations for genetic disorders of the glomerular filtration barrier, with a particular emphasis on how these gene defects cluster by both their ontology and patterns of glomerular pathology.CJASN 15: ccc-ccc, 2020.