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

Author:

Jayadev Ranjay1ORCID,Morais Mychel R. P. T.2ORCID,Ellingford Jamie M.34ORCID,Srinivasan Sandhya1ORCID,Naylor Richard W.2ORCID,Lawless Craig2ORCID,Li Anna S.2ORCID,Ingham Jack F.2ORCID,Hastie Eric1ORCID,Chi Qiuyi1,Fresquet Maryline2ORCID,Koudis Nikki-Maria2ORCID,Thomas Huw B.4ORCID,O’Keefe Raymond T.4ORCID,Williams Emily2ORCID,Adamson Antony5ORCID,Stuart Helen M.34ORCID,Banka Siddharth34ORCID,Smedley Damian6,Sherwood David R.1ORCID,Lennon Rachel27ORCID,

Affiliation:

1. Department of Biology, Duke University, Box 90338, Durham, NC 27708, USA.

2. Wellcome Centre for Cell-Matrix Research, Division of Cell-Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK.

3. Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WL, UK.

4. Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK.

5. Genome Editing Unit Core Facility, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, UK.

6. William Harvey Research Institute, Charterhouse Square, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, EC1M 6BQ London, UK.

7. Department of Paediatric Nephrology, Royal Manchester Children’s Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK.

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 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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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