The Gene Encoding Collagen α1(V) (COL5A1) Is Linked to Mixed Ehlers-Danlos Syndrome Type I/II

Burrows, Nigel; Nicholls, A C; Yates, John R.; Gatward, Graham; Sarathachandra, Padmini; Richards, Allan J.; Pope, F. Michael

doi:10.1111/1523-1747.ep12348978

Cited by 58 publications

(27 citation statements)

References 22 publications

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“…It is now recognized that all fibrils are heterotypic co-assemblies of two or more fibril-forming collagens; a quantitatively major and minor collagen (Birk and Bruckner, 2011). The importance of collagen V has been suggested by studies that modulate its content in model systems, as well as EDS patients (Burrows et al, 1996;1997;De Paepe et al, 1997;Nicholls et al, 1996;Toriello et al, 1996;Wenstrup et al, 1996;Wenstrup et al, 2006;Wenstrup et al, 2011;Bouma et al, 2001).…”

Section: Fibrillogenesis In Col5a1-null Mouse Cornea 4101mentioning

confidence: 99%

Collagen V is a dominant regulator of collagen fibrillogenesis: dysfunctional regulation of structure and function in a corneal-stroma-specificCol5a1-null mouse model

Sun

Chen

Adams

et al. 2011

Journal of Cell Science

147

111

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SummaryCollagen V is a regulatory fibril-forming collagen that forms heterotypic fibrils with collagen I. Deletion of collagen V in the mouse is associated with a lack of fibril assembly in the embryonic mesenchyme, with a resultant lethal phenotype. The current work elucidates the regulatory roles of collagen V during development and growth of tissues. A conditional mouse model with a mutation in Col5a1 was developed using a Cre-loxP approach. Col5a1 was ablated in Col5a1 flox/flox mice using a cornea stroma-specific Kera-Cre driver mouse to produce a bitransgenic Col5a1Dst/Dst line that is null for collagen V. This permits analyses of the corneal stroma, a widely used model for studies of collagen V. The collagen-V-knockout stroma demonstrated severe dysfunctional regulation of fibrillogenesis. Fibril diameters were significantly increased, with an abnormal, heterogeneous distribution; fibril structure was abnormal, fibril number was decreased and lamellae were disorganized with decreased stroma thickness. The phenotype was more severe in the anterior versus posterior stroma. Opacity was demonstrated throughout the Col5a1Dst/Dst stroma, with significantly increased haze intensity compared with control mice. These data indicate central regulatory roles for collagen V in fibril and matrix assembly during tissue development, with dysfunctional regulation resulting in a functional loss of transparency.

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Section: Fibrillogenesis In Col5a1-null Mouse Cornea 4101mentioning

confidence: 99%

Collagen V is a dominant regulator of collagen fibrillogenesis: dysfunctional regulation of structure and function in a corneal-stroma-specificCol5a1-null mouse model

Sun

Chen

Adams

et al. 2011

Journal of Cell Science

147

111

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“…noch unbekannten, die Kollagensynthese hemmenden Enzymdefekten, welche zu einer irregulären Synthese, Strukturanordnung und/oder Integration der Kollagenfasern im Gewebe führen (Burrows 1996(Burrows , 1999.…”

Section: Introductionunclassified

A connective tissue disease of the skin in a foal similiar to the human Ehlers-Danlos Syndrome

Winter¹,

Börgel²,

Aupperle³

et al. 2004

PHK

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ZusammenfassungBeim Ehlers-Danlos Syndrom (E-D S) des Menschen handelt es sich um eine hereditäre Erkrankung des kollagenen Bindegewebes der Haut, welche in vergleichbarer Weise auch bei Tieren beschrieben wird. Von einem sechs Tage alten Oldenburger Stutfohlen mit den klinischen Symptomen einer dermalen Hyperelastizität und -fragilität wurden Gewebeproben der äußeren Haut und Unterhaut histologisch, immunhistologisch und elektronenmikroskopisch untersucht. Lichtmikroskopisch wurde in der Dermis eine irreguläre Anordnung der kollagenen Bindegewebsfasern in Form subepidermaler "Faserplaques" und subkutaner "Faserstränge" nachgewiesen. Im polarisierten Licht der Pikrosiriusrot-Färbung zeigten die "Faserplaques" einen erhöhten Anteil kollagener Fasern des Typs I und die "Faserstränge" einen erhöhten Anteil von Kollagenfasern des Typs III. Mittels Elektronenmikroskopie konnten neben einzelnen regulären Kollagenfibrillen (Durchmesser ca. 140 nm) irreguläre, fragmentierte "Fibrillenplaques" (Größe ca. 240x350 nm) und schlankere "Fibrillenstränge" (Durchmesser variierend zw. 90 und 180 nm) nachgewiesen werden. Darüber hinaus waren im Bereich einzelner größerer subkutaner Venen z.T. hochgradige Panelastofibrosen erkennbar, die einen erhöhten Anteil Kollagenfasern des Typs III aufwiesen. Die erhobenen Befunde lassen den Schluss zu, dass es sich bei dem vorliegenden Fall um eine "E-D S ähnliche kutane Bindegewebserkrankung" bei einem Fohlen handelt.Schlüsselwörter: Ehlers-Danlos Syndrom, Pferd, Hyperfragilität, Kollagenfasern, Haut A connective tissue disease of the skin in a foal similiar to the human Ehlers-Danlos SyndromeThe Ehlers-Danlos syndrome (E-D S) in man is an inherited disease of collagen connective tissue of the skin which is also described in animals. Skin biopsies of a six days old female Oldenburger foal with the clinical signs of fragile and hyperextensive skin were investigated by the use of light microscopical, immunohistochemical and ultrastructural techniques. The results of histopathology revealed an irregular structure of collagen fibres which showed subepidermal fragmented "fibre plaques" and subcutaneous slender "fibre cords". In the polarisation light of the picrosirius-red-stain the "fibre plaques" represented an increased amount of collagen type I while the "fibre cords" showed an increased amount of collagen type III. Electronmicroscopic examination showed some normal sized fibrilles (approx. 140 nm in diameter) and also irregular fragmented "fibrillar plaques" (size: 240x350 nm) and slender "fibrillar cords" (varying from 90 to 180 nm in diameter). In the area of numerous subcutaneous veins a severe panelastofibrosis, containing an increased amount of collagen type III, was present. In the light of the present results, it has been concluded, that this case is an example of a rare, probably idiopathic "E-D S like disease" in a foal.

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“…In addition, laxity in the joints, leading to instability and easy dislocation as well as joint hyper-extensibility, is a characteristic feature resulting from dysfunctional tendons and ligaments. More than half of all instances of classic EDS have been linked to heterozygous mutations in the genes for collagen V (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). The most common mutation type in classic EDS is one that results in a functional loss of one Col5a1 allele (14,15).…”

mentioning

confidence: 99%

Regulation of Collagen Fibril Nucleation and Initial Fibril Assembly Involves Coordinate Interactions with Collagens V and XI in Developing Tendon

Wenstrup

Smith

Florer

et al. 2011

Journal of Biological Chemistry

131

126

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Collagens V and XI comprise a single regulatory type of fibrilforming collagen with multiple isoforms. Both co-assemble with collagen I or II to form heterotypic fibrils and have been implicated in regulation of fibril assembly. The objective of this study was to determine the roles of collagens V and XI in the regulation of tendon fibrillogenesis. Flexor digitorum longus tendons from a haplo-insufficient collagen V mouse model of classic Ehlers Danlos syndrome (EDS) had decreased biomechanical stiffness compared with controls consistent with joint laxity in EDS patients. However, fibril structure was relatively normal, an unexpected finding given the altered fibrils observed in dermis and cornea from this model. This suggested roles for other related molecules, i.e. collagen XI, and compound Col5a1 ؉/؊ ,Col11a1 ؉/؊ tendons had altered fibril structures, supporting a role for collagen XI. To further evaluate this, transcript expression was analyzed in wild type tendons. During development (E18-P10) both collagen V and XI were comparably expressed; however, collagen V predominated in mature (P30) tendons. The collagens had a similar expression pattern. Tendons with altered collagen V and/or XI expression (Col5a1؊/؊ ) were analyzed at E18. All genotypes demonstrated a reduced fibril number and altered structure. This phenotype was more severe with a reduction in collagen XI. However, the absence of collagen XI with a reduction in collagen V was associated with the most severe fibril phenotype. The data demonstrate coordinate roles for collagens V and XI in the regulation of fibril nucleation and assembly during tendon development.Abnormal collagen fibril formation is characteristic of the classic form of Ehlers-Danlos syndrome (EDS).2 Patients with classic EDS (types I and II) have a broad spectrum of generalized connective tissue defects including hyper-extensible skin, fragile skin with wide, depressed, callused scarring, inguinal hernias, and rectal prolapse as well as aortic root dilation and valve prolapse (1, 2). In addition, laxity in the joints, leading to instability and easy dislocation as well as joint hyper-extensibility, is a characteristic feature resulting from dysfunctional tendons and ligaments. More than half of all instances of classic EDS have been linked to heterozygous mutations in the genes for collagen V (3-13). The most common mutation type in classic EDS is one that results in a functional loss of one Col5a1 allele (14, 15).Collagen V is a fibril-forming collagen. The fibril-forming collagen subfamily includes collagens I, II, III, V, XI, XXIV, and XXVII, and the genes cluster into three distinct clades (16). Collagens I, II, and III are the major components of all collagen fibrils. Collagens V and XI are quantitatively minor collagens found as heterotypic fibrils with collagens I, II, and III and have a regulatory function in fibrillogenesis (17). Collagens XXIV and XXVII have structural differences relative to collagens I, II III, V, and XI, and their specific roles remain to be elucida...

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The Gene Encoding Collagen α1(V) (COL5A1) Is Linked to Mixed Ehlers-Danlos Syndrome Type I/II

Cited by 58 publications

References 22 publications

Collagen V is a dominant regulator of collagen fibrillogenesis: dysfunctional regulation of structure and function in a corneal-stroma-specificCol5a1-null mouse model

Collagen V is a dominant regulator of collagen fibrillogenesis: dysfunctional regulation of structure and function in a corneal-stroma-specificCol5a1-null mouse model

A connective tissue disease of the skin in a foal similiar to the human Ehlers-Danlos Syndrome

Regulation of Collagen Fibril Nucleation and Initial Fibril Assembly Involves Coordinate Interactions with Collagens V and XI in Developing Tendon

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