Elovl4 5-bp-deletion knock-in mice develop progressive photoreceptor degeneration

Vidyullatha Vasireddy, Monica Jablonski, Nawajes Mandal, Dorit Raz-Prag, Xiaofei F. Wang, Lesli Nizol, Alessandro Iannaccone, David C. Musch, Ronald A. Bush, Norman Salem, Paul A. Sieving, Radha Ayyagari

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Abstract

PURPOSE. To develop and characterize a heterozygous knock-in mouse model carrying the 5-bp deletion in Elovl4 (E_mut+/-) and to study the pathology underlying Stargardt-like macular degeneration (STGD3). METHODS. E_mut+/- mice were generated by targeting a 5-bp deletion (AACTT) in the Elovl4 gene by homologous recombination. E_mut+/- mice of age 2 to 18 months and age-matched wild-type (Wt) littermate control animals were analyzed for the expression of Elovl4 transcript, ELOVL4 protein, photoreceptor-specific genes, and retinal fatty acid composition. Functional retinal changes were evaluated by electroretinography (ERG) and by morphologic and ultrastructural criteria. RESULTS. E_mut+/- mice retinas showed the presence of both Wt and mutant Elovl4 transcripts and proteins. Morphologic evaluation revealed cone photoreceptor ultrastructural abnormalities as early as 2 months of age, accumulation of lipofuscin in retinal pigment epithelium (RPE), and subretinal deposits at later ages. Shortening of rod outer segments (OS) was observed at ∼10 months of age. Both cone and rod changes progressed with age. Unlike rod-specific genes, expression of selected cone specific genes was significantly reduced by 7 months of age. Mixed rod-cone and light-adapted b-waves were higher than normal at both 8 and 15 months. Levels of the fatty acids 20:5 (P = 0.027), 22:5 (P = 0.040) and 24:6 (P = 0.005) were found to be significantly lower in the retinas of E_mut+/- mice than in retinas of control subjects. CONCLUSIONS. E_mut+/- animals display characteristic features associated with Stargardt-like macular degeneration and serve as a model for the study of the mechanism underlying STGD3.

Original languageEnglish (US)
Pages (from-to)4558-4568
Number of pages11
JournalInvestigative Ophthalmology and Visual Science
Volume47
Issue number10
DOIs
StatePublished - Oct 1 2006

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Retina
Vertebrate Photoreceptor Cells
Fatty Acids
Genes
Retinal Cone Photoreceptor Cells
Rod Cell Outer Segment
Electroretinography
Lipofuscin
Retinal Pigment Epithelium
Homologous Recombination
Proteins
Pathology
Gene Expression
Light
Stargardt disease 1

All Science Journal Classification (ASJC) codes

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Elovl4 5-bp-deletion knock-in mice develop progressive photoreceptor degeneration. / Vasireddy, Vidyullatha; Jablonski, Monica; Mandal, Nawajes; Raz-Prag, Dorit; Wang, Xiaofei F.; Nizol, Lesli; Iannaccone, Alessandro; Musch, David C.; Bush, Ronald A.; Salem, Norman; Sieving, Paul A.; Ayyagari, Radha.

In: Investigative Ophthalmology and Visual Science, Vol. 47, No. 10, 01.10.2006, p. 4558-4568.

Research output: Contribution to journalArticle

Vasireddy, V, Jablonski, M, Mandal, N, Raz-Prag, D, Wang, XF, Nizol, L, Iannaccone, A, Musch, DC, Bush, RA, Salem, N, Sieving, PA & Ayyagari, R 2006, 'Elovl4 5-bp-deletion knock-in mice develop progressive photoreceptor degeneration', Investigative Ophthalmology and Visual Science, vol. 47, no. 10, pp. 4558-4568. https://doi.org/10.1167/iovs.06-0353
Vasireddy, Vidyullatha ; Jablonski, Monica ; Mandal, Nawajes ; Raz-Prag, Dorit ; Wang, Xiaofei F. ; Nizol, Lesli ; Iannaccone, Alessandro ; Musch, David C. ; Bush, Ronald A. ; Salem, Norman ; Sieving, Paul A. ; Ayyagari, Radha. / Elovl4 5-bp-deletion knock-in mice develop progressive photoreceptor degeneration. In: Investigative Ophthalmology and Visual Science. 2006 ; Vol. 47, No. 10. pp. 4558-4568.
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abstract = "PURPOSE. To develop and characterize a heterozygous knock-in mouse model carrying the 5-bp deletion in Elovl4 (E_mut+/-) and to study the pathology underlying Stargardt-like macular degeneration (STGD3). METHODS. E_mut+/- mice were generated by targeting a 5-bp deletion (AACTT) in the Elovl4 gene by homologous recombination. E_mut+/- mice of age 2 to 18 months and age-matched wild-type (Wt) littermate control animals were analyzed for the expression of Elovl4 transcript, ELOVL4 protein, photoreceptor-specific genes, and retinal fatty acid composition. Functional retinal changes were evaluated by electroretinography (ERG) and by morphologic and ultrastructural criteria. RESULTS. E_mut+/- mice retinas showed the presence of both Wt and mutant Elovl4 transcripts and proteins. Morphologic evaluation revealed cone photoreceptor ultrastructural abnormalities as early as 2 months of age, accumulation of lipofuscin in retinal pigment epithelium (RPE), and subretinal deposits at later ages. Shortening of rod outer segments (OS) was observed at ∼10 months of age. Both cone and rod changes progressed with age. Unlike rod-specific genes, expression of selected cone specific genes was significantly reduced by 7 months of age. Mixed rod-cone and light-adapted b-waves were higher than normal at both 8 and 15 months. Levels of the fatty acids 20:5 (P = 0.027), 22:5 (P = 0.040) and 24:6 (P = 0.005) were found to be significantly lower in the retinas of E_mut+/- mice than in retinas of control subjects. CONCLUSIONS. E_mut+/- animals display characteristic features associated with Stargardt-like macular degeneration and serve as a model for the study of the mechanism underlying STGD3.",
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T1 - Elovl4 5-bp-deletion knock-in mice develop progressive photoreceptor degeneration

AU - Vasireddy, Vidyullatha

AU - Jablonski, Monica

AU - Mandal, Nawajes

AU - Raz-Prag, Dorit

AU - Wang, Xiaofei F.

AU - Nizol, Lesli

AU - Iannaccone, Alessandro

AU - Musch, David C.

AU - Bush, Ronald A.

AU - Salem, Norman

AU - Sieving, Paul A.

AU - Ayyagari, Radha

PY - 2006/10/1

Y1 - 2006/10/1

N2 - PURPOSE. To develop and characterize a heterozygous knock-in mouse model carrying the 5-bp deletion in Elovl4 (E_mut+/-) and to study the pathology underlying Stargardt-like macular degeneration (STGD3). METHODS. E_mut+/- mice were generated by targeting a 5-bp deletion (AACTT) in the Elovl4 gene by homologous recombination. E_mut+/- mice of age 2 to 18 months and age-matched wild-type (Wt) littermate control animals were analyzed for the expression of Elovl4 transcript, ELOVL4 protein, photoreceptor-specific genes, and retinal fatty acid composition. Functional retinal changes were evaluated by electroretinography (ERG) and by morphologic and ultrastructural criteria. RESULTS. E_mut+/- mice retinas showed the presence of both Wt and mutant Elovl4 transcripts and proteins. Morphologic evaluation revealed cone photoreceptor ultrastructural abnormalities as early as 2 months of age, accumulation of lipofuscin in retinal pigment epithelium (RPE), and subretinal deposits at later ages. Shortening of rod outer segments (OS) was observed at ∼10 months of age. Both cone and rod changes progressed with age. Unlike rod-specific genes, expression of selected cone specific genes was significantly reduced by 7 months of age. Mixed rod-cone and light-adapted b-waves were higher than normal at both 8 and 15 months. Levels of the fatty acids 20:5 (P = 0.027), 22:5 (P = 0.040) and 24:6 (P = 0.005) were found to be significantly lower in the retinas of E_mut+/- mice than in retinas of control subjects. CONCLUSIONS. E_mut+/- animals display characteristic features associated with Stargardt-like macular degeneration and serve as a model for the study of the mechanism underlying STGD3.

AB - PURPOSE. To develop and characterize a heterozygous knock-in mouse model carrying the 5-bp deletion in Elovl4 (E_mut+/-) and to study the pathology underlying Stargardt-like macular degeneration (STGD3). METHODS. E_mut+/- mice were generated by targeting a 5-bp deletion (AACTT) in the Elovl4 gene by homologous recombination. E_mut+/- mice of age 2 to 18 months and age-matched wild-type (Wt) littermate control animals were analyzed for the expression of Elovl4 transcript, ELOVL4 protein, photoreceptor-specific genes, and retinal fatty acid composition. Functional retinal changes were evaluated by electroretinography (ERG) and by morphologic and ultrastructural criteria. RESULTS. E_mut+/- mice retinas showed the presence of both Wt and mutant Elovl4 transcripts and proteins. Morphologic evaluation revealed cone photoreceptor ultrastructural abnormalities as early as 2 months of age, accumulation of lipofuscin in retinal pigment epithelium (RPE), and subretinal deposits at later ages. Shortening of rod outer segments (OS) was observed at ∼10 months of age. Both cone and rod changes progressed with age. Unlike rod-specific genes, expression of selected cone specific genes was significantly reduced by 7 months of age. Mixed rod-cone and light-adapted b-waves were higher than normal at both 8 and 15 months. Levels of the fatty acids 20:5 (P = 0.027), 22:5 (P = 0.040) and 24:6 (P = 0.005) were found to be significantly lower in the retinas of E_mut+/- mice than in retinas of control subjects. CONCLUSIONS. E_mut+/- animals display characteristic features associated with Stargardt-like macular degeneration and serve as a model for the study of the mechanism underlying STGD3.

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