A basement membrane discovery pipeline uncovers network complexity, regulators, and human disease associations.
A basement membrane discovery pipeline uncovers network complexity, regulators, and human disease associations.
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DOI：
10.1126/sciadv.abn2265
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发表时间：
2022-05-20
期刊：
影响因子：
13.6
通讯作者：
中科院分区：
文献类型：
--
作者：
基底膜（BM）是普遍存在的细胞外基质，其组成仍然难以捉摸，限制了我们对BM调节和功能的理解。通过开发生物信息学和体内发现管道，我们定义了一个由222种人类蛋白质及其动物直系同源物组成的网络，这些蛋白质定位于BM。C.网络分析与筛选线虫和斑马鱼发现了BM调节因子，包括ADAMTS、ROBO和TGFβ。超过100个BM网络基因与人类表型相关，通过筛选来自罕见疾病家族的63，039个基因组，我们在LAMA5，MPZL 2和MATN 2中发现了功能缺失变体，并表明它们调节BM组成和功能。这项跨学科研究确立了BM的巨大复杂性及其对人类健康的影响。基底膜是最古老的动物细胞外基质，成分复杂，与人类疾病密切相关。
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. Basement membrane, the most ancient animal extracellular matrix, has vast component complexity and human disease associations.
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