Late‐onset retinal degeneration pathology due to mutations in CTRP5 is mediated through HTRA1

Abstract

Late‐onset retinal degeneration (L‐ORD) is an autosomal dominant macular degeneration characterized by the formation of sub‐retinal pigment epithelium (RPE) deposits and neuroretinal atrophy. L‐ORD results from mutations in the C1q‐tumor necrosis factor‐5 protein (CTRP5), encoded by the CTRP5/C1QTNF5 gene. To understand the mechanism underlying L‐ORD pathology, we used a human cDNA library yeast two‐hybrid screen to identify interacting partners of CTRP5. Additionally, we analyzed the Bruch's membrane/choroid (BM‐Ch) from wild‐type (Wt), heterozygous S163R Ctrp5 mutation knock‐in (Ctrp5S163R/wt), and homozygous knock‐in (Ctrp5S163R/S163R) mice using mass spectrometry. Both approaches showed an association between CTRP5 and HTRA1 via its C‐terminal PDZ‐binding motif, stimulation of the HTRA1 protease activity by CTRP5, and CTRP5 serving as an HTRA1 substrate. The S163R‐CTRP5 protein also binds to HTRA1 but is resistant to HTRA1‐mediated cleavage. Immunohistochemistry and proteomic analysis showed significant accumulation of CTRP5 and HTRA1 in BM‐Ch of Ctrp5S163R/S163R and Ctrp5S163R/wt mice compared with Wt. Additional extracellular matrix (ECM) components that are HTRA1 substrates also accumulated in these mice. These results implicate HTRA1 and its interaction with CTRP5 in L‐ORD pathology.

Measuring the Contributions of Basal Laminar Deposit and Bruch's Membrane in Age-Related Macular Degeneration

“…45,54,76 Some mouse strains exhibit thin BLamD, and, to date, only models involving the genes listed above have thick BLamD. 66,77 Aged monkeys may naturally exhibit soft drusen, but lack BLamD and do not progress to atrophy or NV, 78 suggesting that BLamD is required for drusen that progress. Indeed, BLamD may share some of the pathophysiology postulated for drusen, with important differences.…”

Autosomal Dominant Gyrate Atrophy-Like Choroidal Dystrophy Revisited: 45 Years Follow-Up and Association with a Novel C1QTNF5 Missense Variant

“…The C1QTNF5 gene product is present in the lateral and basal membrane of retinal pigment epithelial cells and the ciliary body [ 42 ]. It interacts with HTRA1 in mice and affects extracellular matrix turnover, which might explain the development of subretinal deposits in LORD [ 43 , 44 , 45 ]. Following the resolution of X-ray structures of the globular domain of C1QTNF5 [ 16 , 18 ], molecular models were built to explain the mechanism of C1QTNF5-mediated cell adhesion among RPE cells and RPE-Bruch membrane.…”

Quantifying the Separation Between the Retinal Pigment Epithelium and Bruch's Membrane using Optical Coherence Tomography in Patients with Inherited Macular Degeneration

“…Although the exact disease mechanisms are not clear, studies in human postmortem samples and animal models of these inherited macular degenerations have demonstrated that either the proteins themselves, or ECM components modulated by the proteins, aggregate in the BM. [30][31][32] To date, no clinical biomarkers describing the primary pathology underlying these conditions have been reported.…”