Detail
Article
Online article
FT
Medvik - BMC
  • Something wrong with this record ?

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

Language English Country Netherlands

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc21026369

Grant support
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.

References provided by Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc21026369
003      
CZ-PrNML
005      
20211026132945.0
007      
ta
008      
211013s2020 ne f 000 0|eng||
009      
AR
024    7_
$a 10.1016/j.ebiom.2020.103075 $2 doi
035    __
$a (PubMed)33242826
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a ne
100    1_
$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
245    10
$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
520    9_
$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.
650    12
$a alely $7 D000483
650    _2
$a vývojové onemocnění kostí $x diagnóza $x etiologie $x metabolismus $7 D001848
650    _2
$a kosti a kostní tkáň $x abnormality $x diagnostické zobrazování $7 D001842
650    _2
$a buněčná adheze $x genetika $7 D002448
650    _2
$a chondrocyty $x metabolismus $7 D019902
650    _2
$a mutační analýza DNA $7 D004252
650    _2
$a fokální adhezní kinasa 2 $x genetika $x metabolismus $7 D051418
650    _2
$a genetické asociační studie $7 D056726
650    _2
$a genetická predispozice k nemoci $7 D020022
650    _2
$a lidé $7 D006801
650    _2
$a laminin $x genetika $x metabolismus $7 D007797
650    12
$a mutace $7 D009154
650    _2
$a fenotyp $7 D010641
650    12
$a signální transdukce $7 D015398
650    _2
$a signální dráha Wnt $7 D060449
650    _2
$a skupina kinas odvozených od src-genu $x metabolismus $7 D019061
655    _2
$a časopisecké články $7 D016428
700    1_
$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
700    1_
$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
700    1_
$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
700    1_
$a Zhang, Wenjuan $u Department of Molecular, Cell and Developmental Biology, University of California- Los Angeles, Los Angeles, CA 90095, United States
700    1_
$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
700    1_
$a Lachman, Ralph S $u International Skeletal Dysplasia Registry, University of California, Los Angeles, CA 90095 United States
700    1_
$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
700    1_
$a Bamshad, Michael $u University of Washington Center for Mendelian Genomics, University of Washington, Seattle, WA 98195 United States
700    1_
$a Nickerson, Deborah $u University of Washington Center for Mendelian Genomics, University of Washington, Seattle, WA 98195 United States
700    1_
$a Chong, Jessica X $u University of Washington Center for Mendelian Genomics, University of Washington, Seattle, WA 98195 United States
700    1_
$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
700    1_
$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
700    1_
$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
700    1_
$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
773    0_
$w MED00190061 $t EBioMedicine $x 2352-3964 $g Roč. 62, č. - (2020), s. 103075
856    41
$u https://pubmed.ncbi.nlm.nih.gov/33242826 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y p $z 0
990    __
$a 20211013 $b ABA008
991    __
$a 20211026132951 $b ABA008
999    __
$a ok $b bmc $g 1715169 $s 1146876
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2020 $b 62 $c - $d 103075 $e 20201123 $i 2352-3964 $m EBioMedicine $n EBioMedicine $x MED00190061
GRA    __
$a R01 AR066124 $p NIAMS NIH HHS $2 United States
GRA    __
$a UM1 HG006493 $p NHGRI NIH HHS $2 United States
LZP    __
$a Pubmed-20211013

Find record

Citation metrics

Archiving options