Late-onset retinal degeneration pathology de to mutations in CTRP5 is mediated through HTRA1

Anil Chekuri, Katarzyna Zientara-Rytter, Angel Soto-Hermida, Shyamanga Borooah, Marina Voronchikhina, Pooja Biswas, Virendra Kumar, David Goodsell, Caroline Hayward, Peter Shaw, Chloe Stanton, Donita Garland, Suresh Subramani, Radha Ayyagari

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.
Original languageEnglish
Article numbere13011
JournalAging Cell
Issue number6
Early online date5 Aug 2019
Publication statusPublished - Dec 2019


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