@article{844e82ff3b7c4bcda671c21a7e0ed680,
title = "A basement membrane discovery pipeline uncovers network complexity, new regulators, and human disease associations",
abstract = "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 identified new BM regulators, including ADAMTS, ROBO, and TGFb. More than 100 BM-network genes associate with human phenotypes and by screening 63,039 genomes from families with rare disorders, we discovered loss-of-function variants in LAMA5, MPZL2, and MATN2, and show they regulate BM composition and function. This cross-disciplinary study establishes the immense complexity and role of BMs in human health.",
keywords = "Animals, Basement Membrane/metabolism, Caenorhabditis elegans/genetics, Extracellular Matrix/genetics, Extracellular Matrix Proteins/metabolism, Humans, Zebrafish/genetics",
author = "{Genomics England Research Consortium} and Ranjay Jayadev and Morais, {Mychel R P T} and Ellingford, {Jamie M} and Sandhya Srinivasan and Naylor, {Richard W} and Craig Lawless and Li, {Anna S} and Ingham, {Jack F} and Eric Hastie and Qiuyi Chi and Maryline Fresquet and Nikki-Maria Koudis and Thomas, {Huw B} and O'Keefe, {Raymond T} and Emily Williams and Antony Adamson and Stuart, {Helen M} and Siddharth Banka and Damian Smedley and Sherwood, {David R} and Rachel Lennon",
note = "Funding Information: We thank S. Payne, W. Ramos-Lewis, and L. Lewis for assistance with molecular biology; P. Breen and G. Ruvkun for sharing DAF-4::GFP translational reporter strains; staff from the Biomolecular Analysis, Biological Mass Spectrometry, Bioimaging, and Electron Microscopy Core Facilities for advice and assistance; and L. Kelley for discussions. This research was made possible through access to the data and findings generated by the 100KGP. The 100KGP is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100KGP is funded by the National Institute for Health Research and National Health Service England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded research infrastructure. The 100KGP uses data provided by patients and collected by the National Health Service as part of their care and support. This work was supported by the following: Wellcome Senior Fellowship award 202860/Z/16/Z (to R.L.), NIH grants R35GM118049 and R21OD028766 (to D.R.S.), Global Challenge Research Fellowship program (to M.R.P.T.M.), American Cancer Society 129351-PF-16-024-01-CSM (to E.H.), Kidney Research UK grant RP_040_20180306 (to M.F.), Biotechnology and Biological Sciences Research Council award BB/S00047X/1 (to R.T.O. and H.B.T.), National Institute of Child Health and Human Development award R01HD103805-01 (to D.S.), and Wellcome Trust 203128/Z/16/Z (to the Wellcome Centre for Cell-Matrix Research at the University of Manchester). Biotechnology and Biological Sciences Research Council and the University of Manchester Strategic Fund provided funding for equipment. Publisher Copyright: Copyright {\textcopyright} 2022 The Authors,",
year = "2022",
month = may,
day = "20",
doi = "10.1126/sciadv.abn2265",
language = "English",
volume = "8",
journal = "Science Advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science (A A A S)",
number = "20",
}