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@article{1727498,
author = {Barad, M. and Csukasi, F. and Bosáková, Michaela and Martin, J. H. and Zhang, W. J. and Taylor, S. P. and Lachman, R. S. and Zieba, J. and Bamshad, M. and Nickerson, D. and Chong, J. X. and Cohn, D. H. and Krejčí, Pavel and Krakow, D. and Duran, I.},
article_location = {Amsterdam},
article_number = {DEC 2020},
doi = {http://dx.doi.org/10.1016/j.ebiom.2020.103075},
keywords = {Laminin alpha 5; LAMA5; Skeletal dysplasia; Bent bone; beta 1 integrin},
language = {eng},
issn = {2352-3964},
journal = {EBioMedicine},
title = {Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia},
url = {https://www.thelancet.com/pdfs/journals/ebiom/PIIS2352-3964(20)30451-5.pdf},
volume = {62},
year = {2020}
}
TY - JOUR
ID - 1727498
AU - Barad, M. - Csukasi, F. - Bosáková, Michaela - Martin, J. H. - Zhang, W. J. - Taylor, S. P. - Lachman, R. S. - Zieba, J. - Bamshad, M. - Nickerson, D. - Chong, J. X. - Cohn, D. H. - Krejčí, Pavel - Krakow, D. - Duran, I.
PY - 2020
TI - Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia
JF - EBioMedicine
VL - 62
IS - DEC 2020
SP - 1-13
EP - 1-13
PB - Elsevier Science BV
SN - 23523964
KW - Laminin alpha 5
KW - LAMA5
KW - Skeletal dysplasia
KW - Bent bone
KW - beta 1 integrin
UR - https://www.thelancet.com/pdfs/journals/ebiom/PIIS2352-3964(20)30451-5.pdf
L2 - https://www.thelancet.com/pdfs/journals/ebiom/PIIS2352-3964(20)30451-5.pdf
N2 - 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 beta 1 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-beta 1 Integrin-PYK2-FYN focal adhesion complex that regulates skeletogenesis, impacted WNT signaling and, when dysregulated, produced a distinct skeletal disorder. (C) 2020 The Authors. Published by Elsevier B.V.
ER -
BARAD, M., F. CSUKASI, Michaela BOSÁKOVÁ, J. H. MARTIN, W. J. ZHANG, S. P. TAYLOR, R. S. LACHMAN, J. ZIEBA, M. BAMSHAD, D. NICKERSON, J. X. CHONG, D. H. COHN, Pavel KREJČÍ, D. KRAKOW and I. DURAN. Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia. \textit{EBioMedicine}. Amsterdam: Elsevier Science BV, 2020, vol.~62, DEC 2020, p.~1-13. ISSN~2352-3964. Available from: https://dx.doi.org/10.1016/j.ebiom.2020.103075.
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