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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
Language English Country Netherlands
Document type Journal Article
Grant support
R01 AR066124
NIAMS NIH HHS - United States
UM1 HG006493
NHGRI NIH HHS - United States
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- MeSH
- Alleles * MeSH
- Cell Adhesion genetics MeSH
- Chondrocytes metabolism MeSH
- Phenotype MeSH
- Focal Adhesion Kinase 2 genetics metabolism MeSH
- Genetic Predisposition to Disease MeSH
- Genetic Association Studies MeSH
- Bone and Bones abnormalities diagnostic imaging MeSH
- Laminin genetics metabolism MeSH
- Humans MeSH
- Mutation * MeSH
- DNA Mutational Analysis MeSH
- Wnt Signaling Pathway MeSH
- Signal Transduction * MeSH
- src-Family Kinases metabolism MeSH
- Bone Diseases, Developmental diagnosis etiology metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
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.
Department of Biology Faculty of Medicine Masaryk University Brno 62500 Czech Republic
Department of Human Genetics University of California Los Angeles Los Angeles CA 90095 United States
International Clinical Research Center St Anne's University Hospital Brno 65691 Czech Republic
References provided by Crossref.org
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- $a Barad, Maya $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 Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia / $c 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
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- $a 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.
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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 Bamshad, Michael $u University of Washington Center for Mendelian Genomics, University of Washington, Seattle, WA 98195 United States
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