RT Journal Article
T1 Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia
A1 Barad, Maya
A1 Csukasi, Fabiana
A1 Bosakova, Michaela
A1 Martin, Jorge H.
A1 Zhang, Wenjuan
A1 Paige Taylor, S.
A1 Lachman, Ralph S.
A1 Zieba, Jennifer
A1 Bamshad, Michael
A1 Nickerson, Deborah
A1 Chong, Jessica X.
A1 Cohn, Daniel H.
A1 Krejci, Pavel
A1 Krakow, Deborah
A1 Duran, Ivan
K1 Laminin α5
K1 LAMA5
K1 Skeletal dysplasia
K1 Bent bone
K1 β1 integrin
K1 Fibrous dysplasia of bone
K1 Integrina beta1
K1 Displasia fibrosa ósea
AB 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.
PB Elsevier
YR 2020
FD 2020-11-23
LK http://hdl.handle.net/10668/3923
UL http://hdl.handle.net/10668/3923
LA en
NO Barad M, Csukasi F, Bosakova M, Martin JH, Zhang W, Paige Taylor S, et al. Biallelic mutations in LAMA5 disrupts a skeletal noncanonical focal adhesion pathway and produces a distinct bent bone dysplasia. EBioMedicine. 2020 Dec;62:103075
DS RISalud
RD Apr 7, 2025