A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy

Stone, Edwin M.; Lotery, Andrew; Munier, Francis L.; Hèon, Elise; Piguet, B; Guymer, Robyn H.; Vandenburgh, Kimberlie; Cousin, Pascal; Nishimura, Darryl; Swiderski, Ruth E.; Silvestri, G; Mackey, David A.; Hageman, Gregory S.; Bird, Alan C.; Sheffield, Val C.; Schorderet, Daniel F.

doi:10.1038/9722

Cited by 443 publications

(319 citation statements)

References 26 publications

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“…No known human diseases have been associated with fibulin-2 and a fibulin-2 knockout mouse has no obvious elastin phenotype (Chiu, M-L, personal communication). A mutation in fibulin-3 has been implicated in a macular dystrophy (Stone et al, 1999). A fibulin-3 knockout mouse has not yet been described.…”

Section: Fibulinsmentioning

confidence: 99%

New insights into elastic fiber assembly

Wagenseil

Mecham

2007

Birth Defects Research Pt C

355

354

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Elastic fibers provide recoil to tissues that undergo repeated stretch, such as the large arteries and lung. These large extracellular matrix (ECM) structures contain numerous components, and our understanding of elastic fiber assembly is changing as we learn more about the various molecules associated with the assembly process. The main components of elastic fibers are elastin and microfibrils. Elastin makes up the bulk of the mature fiber and is encoded by a single gene. Microfibrils consist mainly of fibrillin, but also contain or associate with proteins such as microfibril associated glycoproteins (MAGPs), fibulins, and EMILIN-1. Microfibrils were thought to facilitate alignment of elastin monomers prior to cross-linking by lysyl oxidase (LOX). We now know that their role, as well as the overall assembly process, is more complex. Elastic fiber formation involves elaborate spatial and temporal regulation of all of the involved proteins and is difficult to recapitulate in adult tissues. This report summarizes the known interactions between elastin and the microfibrillar proteins and their role in elastic fiber assembly based on in vitro studies and evidence from knockout mice. We also propose a model of elastic fiber assembly based on the current data that incorporates interactions between elastin, LOXs, fibulins and the microfibril, as well as the pivotal role played by cells in structuring the final functional fiber. Birth Defects Research (Part C) 81:229-240,

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Section: Fibulinsmentioning

confidence: 99%

New insights into elastic fiber assembly

Wagenseil

Mecham

2007

Birth Defects Research Pt C

355

354

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“…Those heterozygous for the ARMS2/HTRA1 risk allele were at ~2.7 times greater risk of AMD, whereas homozygotes had 8.2 times increased risk (Rivera et al., 2005). Interestingly, a retinal degenerative disease similar to AMD called Doyne honeycomb macular dystrophy was recently discovered to be caused by EFEMP1 coding mutations, and families carrying disease mutations develop drusen and retinal degeneration decades earlier than patients with AMD (Stone et al., 1999). Although there is phenotypic overlap, whether the two diseases are mechanistically linked is not known.…”

Section: Introductionmentioning

confidence: 99%

HTRA1, an age‐related macular degeneration protease, processes extracellular matrix proteins EFEMP1 and TSP1

et al. 2018

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SummaryHigh‐temperature requirement protein A1 (HTRA1) is a serine protease secreted by a number of tissues including retinal pigment epithelium (RPE). A promoter variant of the gene encoding HTRA1 is part of a mutant allele that causes increased HTRA1 expression and contributed to age‐related macular degeneration (AMD) in genomewide association studies. AMD is characterized by pathological development of drusen, extracellular deposits of proteins and lipids on the basal side of RPE. The molecular pathogenesis of AMD is not well understood, and understanding dysregulation of the extracellular matrix may be key. We assess the high‐risk genotype at 10q26 by proteomic comparison of protein levels of RPE cells with and without the mutation. We show HTRA1 protein level is increased in high‐risk RPE cells along with several extracellular matrix proteins, including known HTRA1 cleavage targets LTBP‐1 and clusterin. In addition, two novel targets of HTRA1 have been identified: EFEMP1, an extracellular matrix protein mutated in Doyne honeycomb retinal dystrophy, a genetic eye disease similar to AMD, and thrombospondin 1 (TSP1), an inhibitor of angiogenesis. Our data support the role of RPE extracellular deposition with potential effects in compromised barrier to neovascularization in exudative AMD.

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“…Malattia Leventinese, also known as Doyne honeycomb retinal dystrophy, is characterized by the presence of Bruch's membrane deposits which closely resemble drusen in AMD. A single mutation in the gene encoding fibulin-3 causes all known cases of Malattia Leventinese (Stone et al, 1999). The finding that this disease is caused by a defect in a fibulin protein focused our search for additional macular degeneration-associated fibulin gene mutations, and resulted in the identification of a number of fibulin-5 missense mutations in patients with AMD (Stone et al, 2004).…”

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confidence: 99%

Fibulin-5 distribution in human eyes: Relevance to age-related macular degeneration

Mullins¹,

Olvera²,

Clark³

et al. 2007

Experimental Eye Research

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Fibulin-5 is an extracellular matrix glycoprotein that participates in elastogenesis. Mutations in the gene for fibulin-5 have been found to be associated with age-related macular degeneration. Little is known, however, about the expression of this gene in normal eyes or eyes with age-related macular degeneration. In this study we evaluated the expression of the fibulin-5 protein in human donor eyes and localized this protein to Bruch's membrane and the intercapillary pillars of the choriocapillaris in normal eyes. In eyes with age-related macular degeneration, fibulin-5 was localized to pathologic basal deposits beneath the retinal pigment epithelium as well as some small drusen. These results suggest that fibulin-5 may promote extracellular deposit formation in macular degeneration. Keywordsage-related macular degeneration; fibulins; extracellular matrix; Bruch's membrane Bruch's membrane is a complex structure composed of 5 layers of extracellular matrix located between the retinal pigment epithelium (RPE) and the choriocapillaris. Bruch's membrane plays a number of important roles in normal retinal physiology. Oxygen, glucose and growth factors derived from the choroidal vasculature must pass through this tissue to supply the photoreceptor cells and RPE, while wastes derived from these highly metabolically active cells must pass in the opposite direction to be removed by the choroidal vasculature. In addition, Bruch's membrane is a site for RPE adhesion and also serves as a barrier to neovascularization, as ruptures in this structure are associated with abnormal angiogenesis from the choroid into the retina.During normal aging, and especially in age-related macular degeneration (AMD), Bruch's membrane undergoes morphological changes with extracellular deposit formation. Deposits in Bruch's membrane include drusen and basal deposits (flat and diffuse deposits beneath the Send correspondence to:

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A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy

Cited by 443 publications

References 26 publications

New insights into elastic fiber assembly

New insights into elastic fiber assembly

HTRA1, an age‐related macular degeneration protease, processes extracellular matrix proteins EFEMP1 and TSP1

Fibulin-5 distribution in human eyes: Relevance to age-related macular degeneration

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