Abstract
The pathogenic mutation S163R in C1QTNF5 causes a disorder known as autosomal dominant late-onset retinal degeneration (L-ORD), characterized by the presence of thick extracellular sub-RPE deposits, similar histopathologically to those found in AMD patients. We have previously shown that the S163R C1QTNF5 mutant forms globular aggregates within the RPE in vivo following its AAV-mediated expression in the RPE and exhibits a reversely polarized distribution, being routed toward the basal rather than apical RPE. We show here that when both wild-type and mutant S163R C1QTNF5 are simultaneously delivered subretinally to mouse RPE cells, the mutant impairs the wild-type protein secretion from the RPE, and both proteins are dispersed toward the basal and lateral RPE membrane. This result has mechanistic and therapeutic implications for L-ORD disorder.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Ayyagari R, Mandal MN, Karoukis AJ et al (2005) Late-onset macular degeneration and long anterior lens zonules result from a CTRP5 gene mutation. Invest Ophthalmol Vis Sci 46:3363–3371
Dinculescu A, Min SH, Dyka FM et al (2015) Pathological effects of mutant C1QTNF5 (S163R) expression in murine retinal pigment epithelium. Invest Ophthalmol Vis Sci 56:6971–6980
Hayward C, Shu X, Cideciyan AV et al (2003) Mutation in a short-chain collagen gene, CTRP5, results in extracellular deposit formation in late-onset retinal degeneration: a genetic model for age-related macular degeneration. Hum Mol Genet 12:2657–2667
Jacobson SG, Acland GM, Aguirre GD et al (2006) Safety of recombinant adeno-associated virus type 2-RPE65 vector delivered by ocular subretinal injection. Mol Ther J Am Soc Gene Ther 13:1074–1084
Kuntz CA, Jacobson SG, Cideciyan AV et al (1996) Sub-retinal pigment epithelial deposits in a dominant late-onset retinal degeneration. Invest Ophthalmol Vis Sci 37:1772–1782
Mandal MN, Vasireddy V, Jablonski MM et al (2006a) Spatial and temporal expression of MFRP and its interaction with CTRP5. Invest Ophthalmol Vis Sci 47:5514–5521
Mandal MN, Vasireddy V, Reddy GB et al (2006b) CTRP5 is a membrane-associated and secretory protein in the RPE and ciliary body and the S163R mutation of CTRP5 impairs its secretion. Invest Ophthalmol Vis Sci 47:5505–5513
Schaffler A, Buechler C (2012) CTRP family: linking immunity to metabolism. Trends Endocrinol Metab 23:194–204
Seldin MM, Tan SY, Wong GW (2014) Metabolic function of the CTRP family of hormones. Rev Endocr Metab Disord 15:111–123
Shu X, Tulloch B, Lennon A et al (2006) Disease mechanisms in late-onset retinal macular degeneration associated with mutation in C1QTNF5. Hum Mol Genet 15:1680–1689
Tu X, Palczewski K (2012) Crystal structure of the globular domain of C1QTNF5: implications for late-onset retinal macular degeneration. J Struct Biol 180:439–446
Tu X, Palczewski K (2014) The macular degeneration-linked C1QTNF5 (S163) mutation causes higher-order structural rearrangements. J Struct Biol 186:86–94
Acknowledgments
This study was supported in part by an unrestricted grant from Research to Prevent Blindness, NIH grants EY021721 and EY018331, FFB, and MVRF.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer International Publishing AG, part of Springer Nature
About this paper
Cite this paper
Dinculescu, A. et al. (2018). Co-Expression of Wild-Type and Mutant S163R C1QTNF5 in Retinal Pigment Epithelium. In: Ash, J., Anderson, R., LaVail, M., Bowes Rickman, C., Hollyfield, J., Grimm, C. (eds) Retinal Degenerative Diseases. Advances in Experimental Medicine and Biology, vol 1074. Springer, Cham. https://doi.org/10.1007/978-3-319-75402-4_8
Download citation
DOI: https://doi.org/10.1007/978-3-319-75402-4_8
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-75401-7
Online ISBN: 978-3-319-75402-4
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)