Lens capsule as a model to study type IV collagen

Cummings, Christopher F.; Hudson, Billy G.

doi:10.3109/03008207.2013.867337

Cited by 15 publications

(10 citation statements)

References 38 publications

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“…Moreover, the lens capsule, which surrounds the entire lens, is a prominent basement membrane that contains significant amounts of type IV collagen (Cummings and Hudson, 2014; Bai et al, 2009). To test whether primary lens defects contribute to Col4a1 -related ASD we crossed Col4a1 +/Flex4 1 mice with MLR10 Cre mice, which express CRE as early as E10.5 when the lens vesicle forms (Zhao et al, 2004).…”

Section: Resultsmentioning

confidence: 99%

Genetic dissection of anterior segment dysgenesis caused by aCol4a1mutation

Mao¹,

Kiss

Ou³

et al. 2017

Disease Models &Amp; Mechanisms

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Ocular anterior segment dysgenesis (ASD) describes a spectrum of clinically and genetically heterogeneous congenital disorders affecting anterior structures that often lead to impaired vision. More importantly, 50-75% of patients with ASD develop early onset and aggressive glaucoma. Although several genes have been implicated in the etiology of ASD, the underlying mechanisms remain elusive. Type IV collagen alpha 1 (COL4A1) is an extracellular matrix protein and a critical component of nearly all basement membranes. COL4A1 mutations cause multi-system disorders in patients, including ASD (congenital cataracts, Axenfeld-Rieger's anomaly, Peter's anomaly and microphthalmia) and congenital or juvenile glaucoma. Here, we use a conditional Col4a1 mutation in mice to determine the location and timing of pathogenic events underlying COL4A1-related ocular dysgenesis. Our results suggest that selective expression of the Col4a1 mutation in neural crest cells and their derivatives is not sufficient to cause ocular dysgenesis and that selective expression of the Col4a1 mutation in vascular endothelial cells can lead to mild ASD and optic nerve hypoplasia but only on a sensitized background. In contrast, lens-specific expression of the conditional Col4a1 mutant allele led to cataracts, mild ASD and optic nerve hypoplasia, and age-related intraocular pressure dysregulation and optic nerve damage. Finally, ubiquitous expression of the conditional Col4a1 mutation at distinct developmental stages suggests that pathogenesis takes place before E12.5. Our results show that the lens and possibly vasculature play important roles in Col4a1-related ASD and that the pathogenic events occur at mid-embryogenesis in mice, during early stages of ocular development.

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Section: Resultsmentioning

confidence: 99%

Genetic dissection of anterior segment dysgenesis caused by aCol4a1mutation

Mao¹,

Kiss

Ou³

et al. 2017

Disease Models &Amp; Mechanisms

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“…TEM micrographs of adult human and nonhuman primate retinas, however, showed that the the thickness of the ILM gradually increases with age and reaches up to 2 lm by the age of 80 years ( Fig. 4E-G) [56,69,91]. Furthermore, the ILM develops indentations at its retinal surface that become more pronounced with age ( Fig.…”

Section: Age-dependent Changes Of Bmsmentioning

confidence: 97%

“…The complete composition and the stoichiometries of proteins in BMs have not been determined until recently. Nevertheless, it was known that the LC and other human BMs have a dominant presence of collagen IV . MS now allows a detailed and semiquantitative protein analysis of the in vivo derived BMs .…”

Section: Limitations Of the Current Bm Modelmentioning

confidence: 99%

New concepts in basement membrane biology

et al. 2015

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Basement membranes (BMs) are thin sheets of extracellular matrix that outline epithelia, muscle fibers, blood vessels and peripheral nerves. The current view of BM structure and functions is based mainly on transmission electron microscopy imaging, in vitro protein binding assays, and phenotype analysis of human patients, mutant mice and invertebrata. Recently, MS-based protein analysis, biomechanical testing and cell adhesion assays with in vivo derived BMs have led to new and unexpected insights. Proteomic analysis combined with ultrastructural studies showed that many BMs undergo compositional and structural changes with advancing age. Atomic force microscopy measurements in combination with phenotype analysis have revealed an altered mechanical stiffness that correlates with specific BM pathologies in mutant mice and human patients. Atomic force microscopy-based height measurements strongly suggest that BMs are more than two-fold thicker than previously estimated, providing greater freedom for modelling the large protein polymers within BMs. In addition, data gathered using BMs extracted from mutant mice showed that laminin has a crucial role in BM stability. Finally, recent evidence demonstrate that BMs are bi-functionally organized, leading to the proposition that BM-sidedness contributes to the alternating epithelial and stromal tissue arrangements that are found in all metazoan species. We propose that BMs are ancient structures with tissue-organizing functions and were essential in the evolution of metazoan species.Abbreviations AFM, atomic force microscopy; BM, basement membrane; DN, Descemet's membrane; ECM, extracellular matrix; HSPG, heparan sulfate proteoglycan; ILM, inner limiting membrane; LC, lens capsule; TEM, transmission electron microscopy.

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“…3). The lens is one of the most enriched tissues for type IV collagen 26,27 , and 60% Supplemental Fig. S1A,B.…”

Section: Discussionmentioning

confidence: 99%

The novel missense mutation Met48Lys in FKBP22 changes its structure and functions

Ishikawa

Mizuno

Holden

et al. 2020

Sci Rep

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Mutations in the FKBP14 gene encoding FKBP22 (FK506 Binding Protein 22 kDa) cause kyphoscolioticEhlers-Danlos Syndrome (kEDS). The first clinical report showed that a lack of FKBP22 protein due to mutations causing nonsense-mediated decay of the mRNA leads to a wide spectrum of clinical phenotypes including progressive kyphoscoliosis, joint hypermobility, hypotonia, hyperelastic skin, hearing loss and aortic rupture. Our previous work showed that these phenotypic features could be correlated with the functions of FKBP22, which preferentially binds to type III, VI and X collagens, but not to type I, II or V collagens. We also showed that FKBP22 catalyzed the folding of type III collagen through its prolyl isomerase activity and acted as a molecular chaperone for type III collagen. Recently, a novel missense mutation Met48Lys in FKBP22 was identified in a patient with kEDS. In this report, we expand the list of substrates of FKBP22 and also demonstrate that the Met48Lys mutation diminishes the activities of FKBP22, indicating that pathology can arise from absence of FKBP22, or partial loss of its function.Ehlers-Danlos syndrome (EDS) is an inherited connective tissue disorder mainly characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Thirteen subtypes were classified in the 2017 EDS Nosology 1 and the kyphoscoliotic EDS (kEDS) was recognized as one subtype demonstrating a broader clinical spectrum of phenotypes with major and minor defined criteria. Congenital hypotonia, congenital or early onset kyphoscoliosis, and generalized joint hypermobility with dislocations/subluxations are the major features, and the minor features include skin hyperextensibility, easily bruised skin, rupture/aneurysm of a medium-sized arteries, and osteopenia/osteoporosis among others 1 . While the musculoskeletal symptoms are found in disorders caused by mutations in extracellular matrix (ECM) proteins, in particular collagen which is the most abundant protein in humans 2,3 , kEDS results from the deficiency of two proteins participating in collagen biosynthesis in the rough Endoplasmic Reticulum (rER): the post-translational modifying enzyme Lysyl Hydroxylase 1 (LH1 encoded by PLOD1) 4,5 and the peptidyl-prolyl cis/trans isomerase (PPIase) family protein FK506-binding protein 22 kDa (FKBP22 encoded by FKBP14) 6,7 . The lack of these proteins changes the collagen biosynthetic molecular ensemble in the rER 8-10 , which can lead to the secretion of structurally and/or functionally abnormal collagens 11,12 . Therefore, EDS causative mutations are not restricted to genes coding for ECM molecules but also include genes coding for proteins required for ECM biosynthesis and processing.Proteins are biosynthesized inside the cells following the central dogma that protein information stored in DNA is first transcribed to messenger RNA (mRNA) which is then translated into protein 13,14 . Missense mutations affect this central dogma and alter protein biogenesis in different ways. Depending upon the location of the mu...

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Lens capsule as a model to study type IV collagen

Cited by 15 publications

References 38 publications

Genetic dissection of anterior segment dysgenesis caused by aCol4a1mutation

Genetic dissection of anterior segment dysgenesis caused by aCol4a1mutation

New concepts in basement membrane biology

The novel missense mutation Met48Lys in FKBP22 changes its structure and functions

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