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Silencing the Expression of CTRP5/C1QTNF5 and ELOVL4 Genes by Small Interfering RNA

  • Venkata Ramana Murthy Chavali
  • Vidyullatha Vasireddy
  • Radha AyyagariEmail author
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 723)

Abstract

Two monogenic macular degenerations, the stargardt-like macular degeneration (STGD3) and the late-onset retinal dystrophy (L-ORD), are caused due to mutations in the genes elongation of very long chain fatty acid-4 (ELOVL4) and C1Q tumor necrosis factor-related protein-5 (CTRP5/C1QTNF5) genes, respectively. It has been shown that disease-causing mutations alter the trafficking of these proteins and exert dominant-negative effect. Selective elimination of these mutant proteins may facilitate restoring the normal function of retinal tissue. In this study, we describe characterization of small interfering RNA (siRNA) probes that selectively and effectively knock down the expression of the wild-type and mutant ELOVL4 and the wild-type CTRP5 genes in Cos-7 cells. These probes will be valuable in studying the function of wild-type ELOVL4 and CTRP5 genes, affect of mutant proteins and the potential use of gene silencing in treating STGD3 and L-ORD.

Keywords

CTRP5 C1QTNF5 ELOVL4 siRNA Small interfering RNA Late-onset retinal degeneration STGD3 L-ORD Stargardt-like macular degeneration 

References

  1. Agbaga MP, Brush RS, Mandal MN et al (2008) Role of Stargardt-3 macular dystrophy protein (ELOVL4) in the biosynthesis of very long chain fatty acids. Proc Natl Acad Sci USA 105:12843–12848PubMedCrossRefGoogle Scholar
  2. Ayyagari R, Mandal MA, Karoukis AJ et al (2004) Early-onset long anterior lens zonules and late-onset macular degeneration phenotype is caused by a CTRP5 gene mutation. Invest Ophthalmol Vis Sci 46:3363–3371CrossRefGoogle Scholar
  3. Campbell M, Nguyen AT, Kiang AS et al (2009) An experimental platform for systemic drug delivery to the retina. Proc Natl Acad Sci U S A 106:17817–17822PubMedCrossRefGoogle Scholar
  4. Chavali VR, Sommer JR, Petters RM et al (2010) Identification of a promoter for the human C1Q-tumor necrosis factor-related protein-5 gene associated with late-onset retinal degeneration. Invest Ophthalmol Vis Sci 51:5499–5507PubMedCrossRefGoogle Scholar
  5. Devi GR (2006) siRNA-based approaches in cancer therapy. Cancer Gene Ther 13:819–829PubMedCrossRefGoogle Scholar
  6. 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 12:2657–2667PubMedCrossRefGoogle Scholar
  7. Karan G, Lillo C, Yang Z et al (2005) Lipofuscin accumulation, abnormal electrophysiology, and photoreceptor degeneration in mutant ELOVL4 transgenic mice: a model for macular degeneration. Proc Natl Acad Sci U S A 102:4164–4169PubMedCrossRefGoogle Scholar
  8. Mandal MN, Vasireddy V, Reddy GB et al (2006) 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 47:5505–5513PubMedCrossRefGoogle Scholar
  9. Maugeri A, Meire F, Hoyng CB et al (2004) A novel mutation in the ELOVL4 gene causes autosomal dominant Stargardt-like macular dystrophy. Invest Ophthalmol Vis Sci 45:4263–4267PubMedCrossRefGoogle Scholar
  10. Raz-Prag D, Ayyagari R, Fariss RN et al (2006) Haploinsufficiency is not the key mechanism of pathogenesis in a heterozygous Elovl4 knockout mouse model of STGD3 disease. Invest Ophthalmol Vis Sci 47:3603–3611PubMedCrossRefGoogle Scholar
  11. Shu X, Tulloch B, Lennon A et al (2006a) Disease mechanisms in late-onset retinal macular degeneration associated with mutation in C1QTNF5. Hum Mol Genet 15:1680–1689PubMedCrossRefGoogle Scholar
  12. Shu X, Tulloch B, Lennon A et al (2006b) Biochemical characterisation of the C1QTNF5 gene associated with late-onset retinal degeneration. A genetic model of age-related macular degeneration. Adv Exp Med Biol 572:41–48Google Scholar
  13. Vasireddy V, Wong P, Ayyagari R (2010) Genetics and molecular pathology of Stargardt-like macular degeneration. Prog Retin Eye Res 29(3):191–207PubMedCrossRefGoogle Scholar
  14. Vasireddy V, Vijayasarathy C, Huang J et al (2005) Stargardt-like macular dystrophy protein ELOVL4 exerts a dominant negative effect by recruiting wild-type protein into aggresomes. Mol Vis 11:665–676PubMedGoogle Scholar
  15. Vasireddy V, Jablonski MM, Mandal MN et al (2006) Elovl4 5-bp-deletion knock-in mice develop progressive photoreceptor degeneration. Invest Ophthalmol Vis Sci 47:4558–4568PubMedCrossRefGoogle Scholar
  16. Vasireddy V, Uchida Y, Salem N, Jr. et al (2007) Loss of functional ELOVL4 depletes very long-chain fatty acids (> or = C28) and the unique omega-O-acylceramides in skin leading to neonatal death. Hum Mol Genet 16:471–482PubMedCrossRefGoogle Scholar
  17. Zhang K, Kniazeva M, Han M et al (2001) A 5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy. Nat Genet 27:89–93PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Venkata Ramana Murthy Chavali
    • 1
  • Vidyullatha Vasireddy
    • 1
  • Radha Ayyagari
    • 1
    Email author
  1. 1.Department of Ophthalmology, Shiley Eye CenterUniversity of California San DiegoLa JollaUSA

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