October 2014
Volume 55, Issue 10
Research Highlight  |   October 2014
A Functional Approach to Examine the Role of HTRA1 Versus ARMS2 in AMD
Investigative Ophthalmology & Visual Science October 2014, Vol.55, 6524. doi:10.1167/iovs.14-15670
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      Yingbin Fu; A Functional Approach to Examine the Role of HTRA1 Versus ARMS2 in AMD. Invest. Ophthalmol. Vis. Sci. 2014;55(10):6524. doi: 10.1167/iovs.14-15670.

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      © ARVO (1962-2015); The Authors (2016-present)

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Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly. Numerous studies have shown that chromosome 10q26, which surrounds two genes, HTRA1 and ARMS2, represents one of the two strongest genetic loci associated with AMD. HTRA1 is a multifunctional serine protease that is ubiquitously expressed in mammalian tissues; ARMS2 is primate-specific with largely unknown function. Nine years have passed since the first publication showing the genetic association of 10q26 with AMD. Scientists still cannot agree on the causal allele at this locus, not to mention the underlying pathophysiological mechanism. This is perhaps the biggest genetic mystery in eye research. This dilemma was reflected in a symposium in ARVO 2014, with a topic on the “Genetics and Pathophysiology of AMD: From SNPs to Disease Modeling.” 
In this edition of IOVS, Nakayama et al. 1 performed the first animal study to overexpress human ARMS2 in mice, and to compare the effect of ARMS2 overexpression versus HTRA1 overexpression. Two previous studies have shown that overexpressing HTRA1 in mouse RPE causes defects in the RPE and Bruch's membrane. 2,3 In the current study, the authors used a different approach by transgenically expressing HTRA1 globally. They found that HTRA1 overexpression increases the risk for choroidal neovascularization. This wet AMD phenotype is consistent with previous studies showing that increased HTRA1 in mouse RPE induces polypoidal choroidal vasculopathy. 2,4 In contrast, overexpression of neither ARMS2 nor ARMS2 (A69S), which corresponds to AMD-associated single nucleotide polymorphism rs10490924, causes any significant phenotype in mice. 1 Considering the controversy surrounding the roles of HTRA1 versus ARMS2 in AMD, this study is significant in taking a functional approach to examine their roles in mice. Thus, from a functional perspective, HTRA1 emerges as a strong candidate for AMD. The key missing puzzle piece is now to show that HTRA1 level is indeed increased in AMD eyes. 
Nakayama M Iejima D Akahori M Kamei J Goto A Iwata T. Overexpression of HtrA1 and exposure to mainstream cigarette smoke leads to choroidal neovascularization and subretinal deposits in aged mice. Invest Ophthalmol Vis Sci . 2014; 55: 6514–6523. [CrossRef] [PubMed]
Jones A Kumar S Zhang N Increased expression of multifunctional serine protease, HTRA1, in retinal pigment epithelium induces polypoidal choroidal vasculopathy in mice. Proc Natl Acad Sci U S A . 2011; 108: 14578–14583. [CrossRef] [PubMed]
Vierkotten S Muether PS Fauser S. Overexpression of HTRA1 leads to ultrastructural changes in the elastic layer of Bruch's membrane via cleavage of extracellular matrix components. PLoS One . 2011; 6: e22959. [CrossRef] [PubMed]
Kumar S Berriochoa Z Ambati BK Fu Y. Angiographic features of transgenic mice with increased expression of human serine protease HTRA1 in retinal pigment epithelium. Invest Ophthalmol Vis Sci . 2014; 55: 3842–3850. [CrossRef] [PubMed]

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