CMG2/ANTXR2 regulates extracellular collagen VI which accumulates in hyaline fibromatosis syndrome

Hyaline fibromatosis syndrome (HFS), resulting from ANTXR2 mutations, is an ultra-rare disease that causes intestinal lymphangiectasia and protein-losing enteropathy (PLE). The mechanisms leading to the gastrointestinal phenotype in these patients are not well defined. We present two patients with congenital diarrhea, severe PLE and unique clinical features resulting from deleterious ANTXR2 mutations. Intestinal organoids were generated from one of the patients, along with CRISPR-Cas9 ANTXR2 knockout, and compared with organoids from two healthy controls. The ANTXR2-deficient organoids displayed normal growth and polarity, compared to controls. Using an anthrax-toxin assay we showed that the c.155C>T mutation causes loss-of-function of ANTXR2 protein. An intrinsic defect of monolayer formation in patient-derived or ANTXR2KO organoids was not apparent, suggesting normal epithelial function. However, electron microscopy and second harmonic generation imaging showed abnormal collagen deposition in duodenal samples of these patients. Specifically, collagen VI, which is known to bind ANTXR2, was highly expressed in the duodenum of these patients. In conclusion, despite resistance to anthrax-toxin, epithelial cell function, and specifically monolayer formation, is intact in patients with HFS. Nevertheless, loss of ANTXR2-mediated signaling leads to collagen VI accumulation in the duodenum and abnormal extracellular matrix composition, which likely plays a role in development of PLE.

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Collagen VI as a driver and disease biomarker in human fibrosis

FEBS Journal ◽

10.1111/febs.16039 ◽

2021 ◽

Author(s):

Lynn. Williams ◽

Thomas Layton ◽

Nan Yang ◽

Marc Feldmann ◽

Jagdeep Nanchahal

Keyword(s):

Collagen Vi ◽

Disease Biomarker

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Ligand Binding to the Collagen VI Receptor Triggers a Talin-to-RhoA Switch that Regulates Receptor Endocytosis

Developmental Cell ◽

10.1016/j.devcel.2020.04.015 ◽

2020 ◽

Vol 53 (4) ◽

pp. 418-430.e4

Author(s):

Jérôme Bürgi ◽

Laurence Abrami ◽

Irinka Castanon ◽

Luciano Andres Abriata ◽

Beatrice Kunz ◽

...

Keyword(s):

Ligand Binding ◽

Collagen Vi ◽

Receptor Endocytosis

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Collagen type VI in the human bone marrow microenvironment: a strong cytoadhesive component

Blood ◽

10.1182/blood.v86.5.1740.bloodjournal8651740 ◽

1995 ◽

Vol 86 (5) ◽

pp. 1740-1748 ◽

Cited By ~ 50

Author(s):

G Klein ◽

CA Muller ◽

E Tillet ◽

ML Chu ◽

R Timpl

Keyword(s):

Bone Marrow ◽

Cell Lines ◽

Triple Helix ◽

Collagen Type ◽

Hematopoietic Cell ◽

Human Bone ◽

Human Bone Marrow ◽

Collagen Vi ◽

Collagen Type Vi ◽

Hematopoietic Cell Lines

Collagen type VI, which forms characteristic microfibrillar structures, is assembled from three individual alpha(VI) chains that form a short triple helix and two adjacent globular domains. Expression of all three alpha (VI) collagen chains in the human bone marrow (BM) microenvironment could be detected by chain-specific antibodies in tissue sections and in the adherent stromal layer of long-term BM cultures. In functional studies, collagen type VI was shown to be a strong adhesive substrate for various hematopoietic cell lines and light-density BM mononuclear cells. The adhesive site within the molecule seems to be restricted to the triple helical domain of all three alpha (VI) chains, because individual alpha (VI) chains were not active in the attachment assays. Adhesion of the hematopoietic cell lines to collagen VI was dose-dependent and could be inhibited by heparin. Although the triple helix contains several RGD sequences, adhesion of the hematopoietic cell types to collagen VI could be blocked neither by RGD-containing peptides nor by a neutralizing antibody to the beta 1 integrin subunit. In combination with an antiadhesive substrate, the binding properties of collagen VI could be downregulated. These data suggest that this collagen type may play an important role in the adhesion of hematopoietic cells within the BM microenvironment.

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Collagen VI (COL6)

Science-Business eXchange ◽

10.1038/scibx.2009.103 ◽

2009 ◽

Vol 2 (3) ◽

pp. 103-103

Keyword(s):

Collagen Vi

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Effect of Mechanical Strain on the Collagen VI Pericellular Matrix in Anterior Cruciate Ligament Fibroblasts

Journal of Cellular Physiology ◽

10.1002/jcp.24518 ◽

2014 ◽

Vol 229 (7) ◽

pp. 878-886 ◽

Cited By ~ 9

Author(s):

Francesca Sardone ◽

Francesco Traina ◽

Francesca Tagliavini ◽

Camilla Pellegrini ◽

Luciano Merlini ◽

...

Keyword(s):

Anterior Cruciate Ligament ◽

Cruciate Ligament ◽

Mechanical Strain ◽

Pericellular Matrix ◽

Collagen Vi ◽

Anterior Cruciate

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Cloning and sequence analysis of cDNAs encoding the α1, α2 and α3 chains of mouse collagen VI

Biochemical Journal ◽

10.1042/bj2910787 ◽

1993 ◽

Vol 291 (3) ◽

pp. 787-792 ◽

Cited By ~ 8

Author(s):

R Z Zhang ◽

T C Pan ◽

R Timpl ◽

M L Chu

Keyword(s):

Amino Acid ◽

Amino Acid Sequences ◽

Untranslated Regions ◽

Cdna Libraries ◽

Cdna Clones ◽

Collagen Vi ◽

Central Segment ◽

Glycosylation Sites ◽

Key Features ◽

Triple Helical Domain

cDNA clones encoding the alpha 1, alpha 2 and alpha 3 chains of mouse collagen VI have been isolated by screening cDNA libraries with the corresponding human probes. The composite cDNAs for the alpha 1, alpha 2, and alpha 3 chains are 2.5, 1.6 and 2.9 kb in size respectively. The alpha 1 and alpha 2 cDNAs encode the C-terminal portions of the chains as well as the entire 3′-untranslated regions, while the alpha 3 cDNAs encode a central segment of 959 amino acids flanking the triple-helical domain. The deduced amino acid sequences share 86-88% identity with the human counterparts and 67-73% identity with the chicken equivalents. Alignment of the deduced amino acid sequences of mouse, human and chicken collagens reveal that the key features of the protein, including the cysteine residues, imperfections in the Gly-Xaa-Xaa regions, Arg-Gly-Asp sequences and potential N-glycosylation sites, are mostly conserved.

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Muscle Protein Alterations in LGMD2I Patients With Different Mutations in the Fukutin-related Protein Gene

Journal of Histochemistry & Cytochemistry ◽

10.1369/jhc.2008.951772 ◽

2008 ◽

Vol 56 (11) ◽

pp. 995-1001 ◽

Cited By ~ 11

Author(s):

Lydia U. Yamamoto ◽

Fernando J. Velloso ◽

Bruno L. Lima ◽

Luciana L.Q. Fogaça ◽

Flávia de Paula ◽

...

Keyword(s):

Muscle Protein ◽

Congenital Muscular Dystrophy ◽

Clinical Severity ◽

Variable Degree ◽

Related Protein ◽

Collagen Vi ◽

Rimmed Vacuoles ◽

Calpain 3 ◽

Protein Alterations ◽

Muscle Biopsies

Fukutin-related protein (FKRP) is a protein involved in the glycosylation of cell surface molecules. Pathogenic mutations in the FKRP gene cause both the more severe congenital muscular dystrophy Type 1C and the milder Limb-Girdle Type 2I form (LGMD2I). Here we report muscle histological alterations and the analysis of 11 muscle proteins: dystrophin, four sarcoglycans, calpain 3, dysferlin, telethonin, collagen VI, α-DG, and α2-laminin, in muscle biopsies from 13 unrelated LGMD2I patients with 10 different FKRP mutations. In all, a typical dystrophic pattern was observed. In eight patients, a high frequency of rimmed vacuoles was also found. A variable degree of α2-laminin deficiency was detected in 12 patients through immunofluorescence analysis, and 10 patients presented α-DG deficiency on sarcolemmal membranes. Additionally, through Western blot analysis, deficiency of calpain 3 and dystrophin bands was found in four and two patients, respectively. All the remaining proteins showed a similar pattern to normal controls. These results suggest that, in our population of LGMD2I patients, different mutations in the FKRP gene are associated with several secondary muscle protein reductions, and the deficiencies of α2-laminin and α-DG on sections are prevalent, independently of mutation type or clinical severity.

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