AMACO is a component of the basement membrane-associated Fraser complex.
Fraser syndrome (FS) is a phenotypically variable, autosomal recessive disorder characterized by cryptophthalmus, cutaneous syndactyly, and other malformations resulting from mutations in FRAS1, FREM2, and GRIP1. Transient embryonic epidermal blistering causes the characteristic defects of the disorder. Fras1, Frem1, and Frem2 form the extracellular Fraser complex, which is believed to stabilize the basement membrane. However, several cases of FS could not be attributed to mutations in FRAS1, FREM2, or GRIP1, and FS displays high clinical variability, suggesting that there is an additional genetic, possibly modifying contribution to this disorder. An extracellular matrix protein containing VWA-like domains related to those in matrilins and collagens (AMACO), encoded by the VWA2 gene, has a very similar tissue distribution to the Fraser complex proteins in both mouse and zebrafish. Here, we show that AMACO deposition is lost in Fras1-deficient zebrafish and mice and that Fras1 and AMACO interact directly via their chondroitin sulfate proteoglycan (CSPG) and P2 domains. Knockdown of vwa2, which alone causes no phenotype, enhances the phenotype of hypomorphic Fras1 mutant zebrafish. Together, our data suggest that AMACO represents a member of the Fraser complex.
Institute of Developmental Biology, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, Medical Faculty, University of Cologne, Cologne, Germany.
Rebecca J
RJ
Richardson
Center for Biochemistry, University of Cologne, Cologne, Germany.
Jan M
JM
Gebauer
Institute of Developmental Biology, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, Medical Faculty, University of Cologne, Cologne, Germany.
Jin-Li
JL
Zhang
Center for Biochemistry, University of Cologne, Cologne, Germany.
Birgit
B
Kobbe
Microimaging Center, Shriners Hospital for Children, Portland, Oregon, USA.
Douglas R
DR
Keene
Department of Anatomy I, Medical Faculty, University of Cologne, Cologne, Germany.
Kristina Røkenes
KR
Karlsen
Institute of Developmental Biology, University of Cologne, Cologne, Germany.
Stefânia
S
Richetti
Center for Biochemistry, University of Cologne, Cologne, Germany.
Alexander P
AP
Wohl
Center for Biochemistry, University of Cologne, Cologne, Germany.
Gerhard
G
Sengle
Department of Anatomy I, Medical Faculty, University of Cologne, Cologne, Germany.
Wolfram F
WF
Neiss
Center for Molecular Medicine Cologne, Medical Faculty, University of Cologne, Cologne, Germany; Center for Biochemistry, University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
Mats
M
Paulsson
Institute of Developmental Biology, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, Medical Faculty, University of Cologne, Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany. Electronic address: mhammers@uni-koeln.de.
Matthias
M
Hammerschmidt
Center for Molecular Medicine Cologne, Medical Faculty, University of Cologne, Cologne, Germany; Center for Biochemistry, University of Cologne, Cologne, Germany. Electronic address: raimund.wagener@uni-koeln.de.
Raimund
R
Wagener
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001485:Basement Membrane / Q000378:metabolism*; D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D058497:Fraser Syndrome / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D005808:Genes, Recessive; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; C482018:Fras1 protein, mouse; C575254:Fras1 protein, zebrafish; C504802:Frem2 protein, mouse; C491309:Grip1 protein, mouse; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C549398:VWA2 protein, zebrafish; C480232:Vwa2 protein, mouse; D029961:Zebrafish Proteins