Anti-C1QTNF5 polyclonal antibody

Purpose To (i) describe a series of patients with isolated or syndromic nanophthalmos with the underlying genetic causes, including novel pathogenic variants and their functional characterization and (ii) to study the association of retinal dystrophy in patients withMFRPvariants, based on a detailed literature review of genotype-phenotype correlations. Methods Patients with nanophthalmos and available family members received a comprehensive ophthalmological examination. Genetic analysis was based on whole-exome sequencing and variant calling in core genes includingMFRP, BEST1, TMEM98, PRSS56, CRB1, GJA1, C1QTNF5, MYRFandFAM111A. A minigene assay was performed for functional characterization of a splice site variant. Results Seven patients, aged between three and 65 years, from five unrelated families were included. Novel pathogenic variants inMFRP(c.497C>T, c.899-3C>A, c.1180G>A), andPRSS56(c.1202C>A), and a recurrent de novo variant inFAM111A(c.1706G>A) in a patient with Kenny-Caffey syndrome type 2, were identified. In addition, we report co-inheritance ofMFRP-related nanophthalmos andADAR-related Aicardi-Goutieres syndrome. Conclusion Nanophthalmos is a genetically heterogeneous condition, and the severity of ocular manifestations appears not to correlate with variants in a specific gene. However, retinal dystrophy is only observed in patients harbouring pathogenicMFRPvariants. Furthermore, heterozygous carriers ofMFRPandPRSS56should be screened for the presence of high hyperopia. Identifying nanophthalmos as an isolated condition or as part of a syndrome has implications for counselling and can accelerate the interdisciplinary care of patients.

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 (Ctrp5(S163R/wt)), and homozygous knock-in (Ctrp5(S163R/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 Ctrp5(S163R/S163R) and Ctrp5(S163R/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.