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Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia

M. Barad, F. Csukasi, M. Bosakova, JH. Martin, W. Zhang, S. Paige Taylor, RS. Lachman, J. Zieba, M. Bamshad, D. Nickerson, JX. Chong, DH. Cohn, P. Krejci, D. Krakow, I. Duran

. 2020 ; 62 (-) : 103075. [pub] 20201123

Jazyk angličtina Země Nizozemsko

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc21026369

Grantová podpora
R01 AR066124 NIAMS NIH HHS - United States
UM1 HG006493 NHGRI NIH HHS - United States

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.

Citace poskytuje Crossref.org

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$a Csukasi, Fabiana $u Department of Orthopaedic Surgery, University of California-Los Angeles, 615 Charles E. Young Drive South, BSRB 512, Los Angeles, CA 90095, United States; Laboratory of Bioengineering and Tissue Regeneration-LABRET, Department of Cell Biology, Genetics and Physiology, University of Málaga, IBIMA, Málaga 29071, Spain
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$a Bosakova, Michaela $u Department of Biology, Faculty of Medicine, Masaryk University, Brno 62500, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Brno 65691, Czech Republic
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$a Martin, Jorge H $u Department of Orthopaedic Surgery, University of California-Los Angeles, 615 Charles E. Young Drive South, BSRB 512, Los Angeles, CA 90095, United States
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$a Zhang, Wenjuan $u Department of Molecular, Cell and Developmental Biology, University of California- Los Angeles, Los Angeles, CA 90095, United States
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$a Paige Taylor, S $u Department of Orthopaedic Surgery, University of California-Los Angeles, 615 Charles E. Young Drive South, BSRB 512, Los Angeles, CA 90095, United States
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$a Lachman, Ralph S $u International Skeletal Dysplasia Registry, University of California, Los Angeles, CA 90095 United States
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$a Zieba, Jennifer $u Department of Orthopaedic Surgery, University of California-Los Angeles, 615 Charles E. Young Drive South, BSRB 512, Los Angeles, CA 90095, United States
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$a Bamshad, Michael $u University of Washington Center for Mendelian Genomics, University of Washington, Seattle, WA 98195 United States
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$a Nickerson, Deborah $u University of Washington Center for Mendelian Genomics, University of Washington, Seattle, WA 98195 United States
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$a Chong, Jessica X $u University of Washington Center for Mendelian Genomics, University of Washington, Seattle, WA 98195 United States
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$a Cohn, Daniel H $u Department of Orthopaedic Surgery, University of California-Los Angeles, 615 Charles E. Young Drive South, BSRB 512, Los Angeles, CA 90095, United States; Department of Molecular, Cell and Developmental Biology, University of California- Los Angeles, Los Angeles, CA 90095, United States; Orthopaedic Institute for Children, University of California-Los Angeles, Los Angeles, CA 90095, United States
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$a Krejci, Pavel $u Department of Biology, Faculty of Medicine, Masaryk University, Brno 62500, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Brno 65691, Czech Republic
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$a Krakow, Deborah $u Department of Orthopaedic Surgery, University of California-Los Angeles, 615 Charles E. Young Drive South, BSRB 512, Los Angeles, CA 90095, United States; International Skeletal Dysplasia Registry, University of California, Los Angeles, CA 90095 United States; Orthopaedic Institute for Children, University of California-Los Angeles, Los Angeles, CA 90095, United States; Department of Human Genetics, University of California-Los Angeles, Los Angeles, CA 90095, United States; Department of Obstetrics and Gynecology, University of California-Los Angeles, Los Angeles, CA 90095, United States. Electronic address: dkrakow@mednet.ucla.edu
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$a Duran, Ivan $u Department of Orthopaedic Surgery, University of California-Los Angeles, 615 Charles E. Young Drive South, BSRB 512, Los Angeles, CA 90095, United States; Laboratory of Bioengineering and Tissue Regeneration-LABRET, Department of Cell Biology, Genetics and Physiology, University of Málaga, IBIMA, Málaga 29071, Spain; Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Andalusian Centre for Nanomedicine and Biotechnology-BIONAND, Severo Ochoa 35, Málaga 29590, Spain
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