Novel defects in collagen XII and VI expand the mixed myopathy/Ehlers–Danlos syndrome spectrum and lead to variant-specific alterations in the extracellular matrix

Delbaere, Sarah; Dhooge, Tibbe; Syx, Delfien; Petit, Florence; Goemans, Nathalie; Destrée, Anne; Vanakker, Olivier; Rycke, Riet De; Symoens, Sofie; Malfait, Fransiska

doi:10.1038/s41436-019-0599-6

Cited by 37 publications

(46 citation statements)

References 37 publications

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“…Collagen V is a regulator of collagen fibril formation, matrix assembly and tissue function in the corneal stroma 29 . Pathogenic variants in COL12A1, COL6A1, COL1A1, and COL5A1 have been described in individuals with different subtypes of the connective tissue disorders Ehlers-Danlos Syndrome and osteogenesis imperfecta [30][31][32][33] .…”

Section: Resultsmentioning

confidence: 99%

A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus

et al. 2021

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Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease.

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Section: Resultsmentioning

confidence: 99%

A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus

et al. 2021

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“…Interestingly, the sequence variants in DCN and FMOD are also associated with ACL injury [ 23 ]. In addition, the extracellular decrease of decorin was found in the cell culture of dermal fibroblasts obtained from mEDS patients [ 24 ], and the mice deficient for decorin or fibromodulin demonstrate abnormal fibrillar organization and decreased mechanical properties in tendons and cornea [ 25 , 26 , 27 , 28 ]. These data suggest that collagen XII regulates fibrillogenesis via interacting with other extracellular molecules, thereby maintaining tissue stability and mechanical strength.…”

Section: Discussionmentioning

confidence: 99%

“…Further studies are required. On the other hand, collagens V and VI are functionally interacted in the cell-matrix environment [ 24 , 31 ]. Collagen VI- and XII-related disorders share clinical overlaps [ 17 , 18 , 24 ], and our previous study demonstrated a functional relationship between collagens VI and XII during osteogenesis [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Collagen XII Deficiency Increases the Risk of Anterior Cruciate Ligament Injury in Mice

Fukusato

Nagao

Fujihara

et al. 2021

JCM

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Anterior cruciate ligament (ACL) rupture is a common knee injury for athletes. Although surgical reconstruction is recommended for the treatment of ACL ruptures, 100% functional recovery is unlikely. Therefore, the discovery of risk factors for ACL ruptures may prevent injury. Several studies have reported an association between polymorphisms of the collagen XII gene COL12A1 and ACL rupture. Collagen XII is highly expressed in tendons and ligaments and regulates tissue structure and mechanical property. Therefore, we hypothesized that collagen XII deficiency may cause ACL injury. To elucidate the influence of collagen XII deficiency on ACL, we analyzed a mouse model deficient for Col12a1. Four- to 19-week-old male Col12a1-/- and wild-type control mice were used for gait analysis; histological and immunofluorescent analysis of collagen XII, and real-time RT-PCR evaluation of Col12a1 mRNA expression. The Col12a1-/- mice showed an abnormal gait with an approximately 2.7-fold increase in step angle, suggesting altered step alignment. Col12a1-/- mice displayed 20–60% ACL discontinuities, but 0% discontinuity in the posterior cruciate ligament. No discontinuities in knee ligaments were found in wild-type mice. Collagen XII mRNA expression in the ACL tended to decrease with aging. Our study demonstrates for the first time that collagen XII deficiency increases the risk of ACL injury.

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“…Recently, it has been shown that human mutations in collagen XII in human skin are associated with decreased expression of tenascin X and decorin, both well-known regulators of fibril diameter. 33 , 34 More research is needed regarding the relevance of collagen XII expression compared to proteoglycans expressed in the matrix. Collagen XII itself, by interacting with different matrix components, including collagen I, or by regulating tissue mechanics, may have multiple regulatory functions in the stroma.…”

Section: Discussionmentioning

confidence: 99%

Collagen XII Is a Regulator of Corneal Stroma Structure and Function

Sun

Zafrullah

Devaux

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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The aim of this study was to determine the roles of collagen XII in the regulation of stromal hierarchical organization, keratocyte organization, and corneal mechanics. METHODS. The temporal and spatial expression of collagen XII at postnatal days 4, 10, 30, 90, and 150 were evaluated in wild-type (WT) mice. The role of collagen XII in hierarchical organization was analyzed by measuring fibril diameter and density, as well as stromal lamellar structure, within ultrastructural micrographs obtained from WT and collagen XIIdeficient mice (Col12a1-/-). Keratocyte morphology and networks were assessed using actin staining with phalloidin and in vivo confocal microscopy. The effects of collagen XII on corneal biomechanics were evaluated with atomic force microscopy. RESULTS. Collagen XII was localized homogeneously in the stroma from postnatal day 4 to day 150, and protein accumulation was shown to increase during this period using semiquantitative immunoblots. Higher fibril density (P < 0.001) and disruption of lamellar organization were found in the collagen XII null mice stroma when compared to WT mice. Keratocyte networks and organization were altered in the absence of collagen XII, as demonstrated using fluorescent microscopy after phalloidin staining and in vivo confocal microscopy. Corneal stiffness was increased in the absence of collagen XII. Young's modulus was 16.2 ± 5.6 kPa in WT and 32.8 ± 6.4 kPa in Col12a1-/corneas. The difference between these two groups was significant (P < 0.001, t-test). CONCLUSIONS. Collagen XII plays a major role in establishing and maintaining stromal structure and function. In the absence of collagen XII, the corneal stroma showed significant abnormalities, including decreased interfibrillar space, disrupted lamellar organization, abnormal keratocyte organization, and increased corneal stiffness.

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Novel defects in collagen XII and VI expand the mixed myopathy/Ehlers–Danlos syndrome spectrum and lead to variant-specific alterations in the extracellular matrix

Cited by 37 publications

References 37 publications

A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus

A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus

Collagen XII Deficiency Increases the Risk of Anterior Cruciate Ligament Injury in Mice

Collagen XII Is a Regulator of Corneal Stroma Structure and Function

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