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L\u2010ORD results from mutations in the C1q\u2010tumor necrosis factor\u20105 protein (CTRP5), encoded by the <jats:italic>CTRP5\/C1QTNF5 gene<\/jats:italic>. To understand the mechanism underlying L\u2010ORD pathology, we used a human cDNA library yeast two\u2010hybrid screen to identify interacting partners of CTRP5. Additionally, we analyzed the Bruch's membrane\/choroid (BM\u2010Ch) from wild\u2010type (<jats:italic>Wt<\/jats:italic>), heterozygous S163R <jats:italic>Ctrp5<\/jats:italic> mutation knock\u2010in (<jats:italic>Ctrp5<jats:sup>S163R\/wt<\/jats:sup><\/jats:italic>), and homozygous knock\u2010in <jats:italic>(Ctrp5<jats:sup>S163R\/S163R<\/jats:sup><\/jats:italic>) mice using mass spectrometry. Both approaches showed an association between CTRP5 and HTRA1 via its C\u2010terminal PDZ\u2010binding motif, stimulation of the HTRA1 protease activity by CTRP5, and CTRP5 serving as an HTRA1 substrate. The S163R\u2010CTRP5 protein also binds to HTRA1 but is resistant to HTRA1\u2010mediated cleavage. Immunohistochemistry and proteomic analysis showed significant accumulation of CTRP5 and HTRA1 in BM\u2010Ch of <jats:italic>Ctrp5<jats:sup>S163R\/S163R<\/jats:sup><\/jats:italic> and <jats:italic>Ctrp5<jats:sup>S163R\/wt<\/jats:sup><\/jats:italic> mice compared with <jats:italic>Wt<\/jats:italic>. 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\u2010ORD pathology.<\/jats:p>","DOI":"10.1111\/acel.13011","type":"journal-article","created":{"date-parts":[[2019,8,6]],"date-time":"2019-08-06T04:54:46Z","timestamp":1565067286000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Late\u2010onset retinal degeneration pathology due to mutations in CTRP5 is mediated through HTRA1"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0652-2630","authenticated-orcid":false,"given":"Anil","family":"Chekuri","sequence":"first","affiliation":[{"name":"Shiley Eye Institute University of California San Diego San Diego CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9352-1758","authenticated-orcid":false,"given":"Katarzyna","family":"Zientara\u2010Rytter","sequence":"additional","affiliation":[{"name":"Division of 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