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oai:repisalud.isciii.es:20.500.12105/181602024-11-28T15:29:41Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16927
Repisalud author Barad, Maya author Csukasi, Fabiana author Bosakova, Michaela author Martin, Jorge H. author Zhang, Wenjuan author Paige Taylor, S. author Lachman, Ralph S. author Zieba, Jennifer author Bamshad, Michael author Nickerson, Deborah author Chong, Jessica X. author Cohn, Daniel H. author Krejci, Pavel author Krakow, Deborah author Duran, Ivan authoraffiliation [Barad,M; Csukasi,F; Martin,JH; Paige Taylor,S; Zieba,J; Cohn,DH; Krakow,D; Duran,I] Department of Orthopaedic Surgery, University of California-Los Angeles, CA, United States. [Csukasi,F; Duran,I] Laboratory of Bioengineering and Tissue Regeneration-LABRET, Department of Cell Biology, Genetics and Physiology, University of Malaga, IBIMA, Málaga,Spain. [Bosakova,M; Krejci,P] Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic. [Bosakova,M; Krejci,P] International Clinical Research Center, St. Anne’s University Hospital, Brno, Czech Republic. [Zhang,W; Cohn,DH] Department of Molecular, Cell and Developmental Biology, University of California-Los Angeles, CA, United States. [Lachman,RS; Krakow,D] International Skeletal Dysplasia Registry, University of California, Los Angeles, United States. [Bamshad,M; Nickerson,D; Chong,JX] University of Washington Center for Mendelian Genomics, University of Washington, Seattle, WA, United States. [Cohn,DH; Krakow,D] Orthopaedic Institute for Children, University of California Los Angeles, Los Angeles, CA, United States. [Krakow,D] Department of Human Genetics, University of California-Los Angeles, CA, United States. [Durán,I] Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Andalusian Centre for Nanomedicine and Biotechnology-BIONAND, Málaga, Spain. 2024-02-12T19:48:06Z 2024-02-12T19:48:06Z 2020-11-23 10.1016/j.ebiom.2020.103075 2352-3964 EBioMedicine http://hdl.handle.net/10668/3923 33242826 http://hdl.handle.net/20.500.12105/18160 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 b1 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-b1 Integrin-PYK2-FYN focal adhesion complex that regulates skeletogenesis, impacted WNT signaling and, when dysregulated, produced a distinct skeletal disorder. eng Laminin α5 LAMA5 Skeletal dysplasia Bent bone β1 integrin Fibrous dysplasia of bone Integrina beta1 Displasia fibrosa ósea Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia research article