Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia
Year: 2020
Type: article
Abstract: BACKGROUND: Beyond its structural role in the skeleton, the extracellular matrix (ECM), particularly basement membrane proteins, facilitates communication with intracellular signaling pathways and cell to cell interactions to control differentiation, proliferation, migration and survival. Alterations in extracellular proteins cause a number of skeletal disorders, yet the consequences of an abnormal ECM on cellular communication remains less well understood METHODS: Clinical and radiographic examinations defined the phenotype in this unappreciated bent bone skeletal disorder. Exome analysis identified the genetic alteration, confirmed by Sanger sequencing. Quantitative PCR, western blot analyses, immunohistochemistry, luciferase assay for WNT signaling were employed to determine RNA, proteins levels and localization, and dissect out the underlying cell signaling abnormalities. Migration and wound healing assays examined cell migration properties. FINDINGS: This bent bone dysplasia resulted from biallelic mutations in LAMA5, the gene encoding the alpha-5 laminin basement membrane protein. This finding uncovered a mechanism of disease driven by ECM-cell interactions between alpha-5-containing laminins, and integrin-mediated focal adhesion signaling, particularly in cartilage. Loss of LAMA5 altered β1 integrin signaling through the non-canonical kinase PYK2 and the skeletal enriched SRC kinase, FYN. Loss of LAMA5 negatively impacted the actin cytoskeleton, vinculin localization, and WNT signaling. INTERPRETATION: This newly described mechanism revealed a LAMA5-β1 Integrin-PYK2-FYN focal adhesion complex that regulates skeletogenesis, impacted WNT signaling and, when dysregulated, produced a distinct skeletal disorder. FUNDING: Supported by NIH awards R01 AR066124, R01 DE019567, R01 HD070394, and U54HG006493, and Czech Republic grants INTER-ACTION LTAUSA19030, V18-08-00567 and GA19-20123S.
Source: EBioMedicine
Institutions: University of California, Los Angeles, Instituto de Investigación Biomédica de Málaga, Universidad de Málaga, Masaryk University, International Clinical Research Center, St. Anne's University Hospital Brno, St. Anne's University Hospital Brno, University of Washington, Orthopaedic Institute for Children, Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine, Andalusian Centre for Nanomedicine and Biotechnology
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,500
Funders: Technology Agency of the Czech Republic, Grantová Agentura České Republiky, National Institutes of Health, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institute of Dental and Craniofacial Research
Awards: Low stability of FGF morphogens in regulation of early mammalian limb development, UW Center for Mendelian Genomics, Unraveling the mechanisms of prenatal-onset disorders affecting the skeleton, Short-rib polydactyly and the skeletal ciliopathies, UW Center for Mendelian Genomics, G8647714995, G9000096724, G9000271908
OpenAlex ID: W3093073199