A basement membrane discovery pipeline uncovers network complexity, regulators, and human disease associations.

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.

Citation

Ranjay Jayadev, Mychel R P T Morais, Jamie M Ellingford, Sandhya Srinivasan, Richard W Naylor, Craig Lawless, Anna S Li, Jack F Ingham, Eric Hastie, Qiuyi Chi, Maryline Fresquet, Nikki-Maria Koudis, Huw B Thomas, Raymond T O'Keefe, Emily Williams, Antony Adamson, Helen M Stuart, Siddharth Banka, Damian Smedley, Genomics England Research Consortium, David R Sherwood, Rachel Lennon. A basement membrane discovery pipeline uncovers network complexity, regulators, and human disease associations. Science advances. 2022 May 20;8(20):eabn2265

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PMID: 35584218

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