Haploinsufficiency is not the key mechanism of pathogenesis in a heterozygous Elovl4 knockout mouse model of STGD3 disease

Dorit Raz-Prag, Radha Ayyagari, Robert N. Fariss, Nawajes Mandal, Vidyullatha Vasireddy, Sharon Majchrzak, Andrea L. Webber, Ronald A. Bush, J. Norman Salem, Konstantin Petrukhin, Paul A. Sieving

Research output: Contribution to journalArticle

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Abstract

PURPOSE. Autosomal dominant Stargardt-like (STGD3) disease results from mutations in the ELOVL4 gene (elongation of very-long-chain fatty acids). This study was undertaken to characterize a mouse model with a targeted deletion of Elovl4 and to explore the role of this gene in retinal/macular degeneration. METHODS. A construct targeted to exon 2 of the Elovl4 gene was used to suppress expression of the gene. Elovl4 homozygous pups were nonviable and were not available for study. Hence, the analysis was performed on heterozygous Elovl4+/- mice 16 to 22 month of age and littermate wild-type (WT) control mice of the same age. Characterization included examining gene message and protein levels, electroretinogram (ERG), retinal morphology and ultrastructure, and plasma and retinal fatty acid composition. RESULTS. Although the level of Elovl4 mRNA was reduced in Elovl4+/- retinas, only minimal morphologic abnormalities were found, and the retinal (ERG) function was essentially normal in Elovl4+/- retinas compared with the WT control retinas. Systemic fatty acid profiles of Elovl4+/- mice were unremarkable, although the concentration of several fatty acids was significantly lower in Elovl4+/- retinas, particularly the monounsaturated fatty acids. CONCLUSIONS. The detailed characterization of this animal model provides the first in vivo evidence that Elovl4 haploinsufficiency is not the underlying key disease mechanism in STGD3. The results are consistent with a dominant negative mechanism for the deletion mutation. The Elovl4 knockout mouse is one of three complementary animal models that will help elucidate the disease mechanism.

Original languageEnglish (US)
Pages (from-to)3603-3611
Number of pages9
JournalInvestigative Ophthalmology and Visual Science
Volume47
Issue number8
DOIs
StatePublished - Aug 1 2006
Externally publishedYes

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Haploinsufficiency
Knockout Mice
Retina
Fatty Acids
Animal Models
Genes
Monounsaturated Fatty Acids
Retinal Degeneration
Sequence Deletion
Macular Degeneration
Exons
Gene Expression
Messenger RNA
Mutation
Proteins

All Science Journal Classification (ASJC) codes

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Haploinsufficiency is not the key mechanism of pathogenesis in a heterozygous Elovl4 knockout mouse model of STGD3 disease. / Raz-Prag, Dorit; Ayyagari, Radha; Fariss, Robert N.; Mandal, Nawajes; Vasireddy, Vidyullatha; Majchrzak, Sharon; Webber, Andrea L.; Bush, Ronald A.; Norman Salem, J.; Petrukhin, Konstantin; Sieving, Paul A.

In: Investigative Ophthalmology and Visual Science, Vol. 47, No. 8, 01.08.2006, p. 3603-3611.

Research output: Contribution to journalArticle

Raz-Prag, D, Ayyagari, R, Fariss, RN, Mandal, N, Vasireddy, V, Majchrzak, S, Webber, AL, Bush, RA, Norman Salem, J, Petrukhin, K & Sieving, PA 2006, 'Haploinsufficiency is not the key mechanism of pathogenesis in a heterozygous Elovl4 knockout mouse model of STGD3 disease', Investigative Ophthalmology and Visual Science, vol. 47, no. 8, pp. 3603-3611. https://doi.org/10.1167/iovs.05-1527
Raz-Prag, Dorit ; Ayyagari, Radha ; Fariss, Robert N. ; Mandal, Nawajes ; Vasireddy, Vidyullatha ; Majchrzak, Sharon ; Webber, Andrea L. ; Bush, Ronald A. ; Norman Salem, J. ; Petrukhin, Konstantin ; Sieving, Paul A. / Haploinsufficiency is not the key mechanism of pathogenesis in a heterozygous Elovl4 knockout mouse model of STGD3 disease. In: Investigative Ophthalmology and Visual Science. 2006 ; Vol. 47, No. 8. pp. 3603-3611.
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abstract = "PURPOSE. Autosomal dominant Stargardt-like (STGD3) disease results from mutations in the ELOVL4 gene (elongation of very-long-chain fatty acids). This study was undertaken to characterize a mouse model with a targeted deletion of Elovl4 and to explore the role of this gene in retinal/macular degeneration. METHODS. A construct targeted to exon 2 of the Elovl4 gene was used to suppress expression of the gene. Elovl4 homozygous pups were nonviable and were not available for study. Hence, the analysis was performed on heterozygous Elovl4+/- mice 16 to 22 month of age and littermate wild-type (WT) control mice of the same age. Characterization included examining gene message and protein levels, electroretinogram (ERG), retinal morphology and ultrastructure, and plasma and retinal fatty acid composition. RESULTS. Although the level of Elovl4 mRNA was reduced in Elovl4+/- retinas, only minimal morphologic abnormalities were found, and the retinal (ERG) function was essentially normal in Elovl4+/- retinas compared with the WT control retinas. Systemic fatty acid profiles of Elovl4+/- mice were unremarkable, although the concentration of several fatty acids was significantly lower in Elovl4+/- retinas, particularly the monounsaturated fatty acids. CONCLUSIONS. The detailed characterization of this animal model provides the first in vivo evidence that Elovl4 haploinsufficiency is not the underlying key disease mechanism in STGD3. The results are consistent with a dominant negative mechanism for the deletion mutation. The Elovl4 knockout mouse is one of three complementary animal models that will help elucidate the disease mechanism.",
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T1 - Haploinsufficiency is not the key mechanism of pathogenesis in a heterozygous Elovl4 knockout mouse model of STGD3 disease

AU - Raz-Prag, Dorit

AU - Ayyagari, Radha

AU - Fariss, Robert N.

AU - Mandal, Nawajes

AU - Vasireddy, Vidyullatha

AU - Majchrzak, Sharon

AU - Webber, Andrea L.

AU - Bush, Ronald A.

AU - Norman Salem, J.

AU - Petrukhin, Konstantin

AU - Sieving, Paul A.

PY - 2006/8/1

Y1 - 2006/8/1

N2 - PURPOSE. Autosomal dominant Stargardt-like (STGD3) disease results from mutations in the ELOVL4 gene (elongation of very-long-chain fatty acids). This study was undertaken to characterize a mouse model with a targeted deletion of Elovl4 and to explore the role of this gene in retinal/macular degeneration. METHODS. A construct targeted to exon 2 of the Elovl4 gene was used to suppress expression of the gene. Elovl4 homozygous pups were nonviable and were not available for study. Hence, the analysis was performed on heterozygous Elovl4+/- mice 16 to 22 month of age and littermate wild-type (WT) control mice of the same age. Characterization included examining gene message and protein levels, electroretinogram (ERG), retinal morphology and ultrastructure, and plasma and retinal fatty acid composition. RESULTS. Although the level of Elovl4 mRNA was reduced in Elovl4+/- retinas, only minimal morphologic abnormalities were found, and the retinal (ERG) function was essentially normal in Elovl4+/- retinas compared with the WT control retinas. Systemic fatty acid profiles of Elovl4+/- mice were unremarkable, although the concentration of several fatty acids was significantly lower in Elovl4+/- retinas, particularly the monounsaturated fatty acids. CONCLUSIONS. The detailed characterization of this animal model provides the first in vivo evidence that Elovl4 haploinsufficiency is not the underlying key disease mechanism in STGD3. The results are consistent with a dominant negative mechanism for the deletion mutation. The Elovl4 knockout mouse is one of three complementary animal models that will help elucidate the disease mechanism.

AB - PURPOSE. Autosomal dominant Stargardt-like (STGD3) disease results from mutations in the ELOVL4 gene (elongation of very-long-chain fatty acids). This study was undertaken to characterize a mouse model with a targeted deletion of Elovl4 and to explore the role of this gene in retinal/macular degeneration. METHODS. A construct targeted to exon 2 of the Elovl4 gene was used to suppress expression of the gene. Elovl4 homozygous pups were nonviable and were not available for study. Hence, the analysis was performed on heterozygous Elovl4+/- mice 16 to 22 month of age and littermate wild-type (WT) control mice of the same age. Characterization included examining gene message and protein levels, electroretinogram (ERG), retinal morphology and ultrastructure, and plasma and retinal fatty acid composition. RESULTS. Although the level of Elovl4 mRNA was reduced in Elovl4+/- retinas, only minimal morphologic abnormalities were found, and the retinal (ERG) function was essentially normal in Elovl4+/- retinas compared with the WT control retinas. Systemic fatty acid profiles of Elovl4+/- mice were unremarkable, although the concentration of several fatty acids was significantly lower in Elovl4+/- retinas, particularly the monounsaturated fatty acids. CONCLUSIONS. The detailed characterization of this animal model provides the first in vivo evidence that Elovl4 haploinsufficiency is not the underlying key disease mechanism in STGD3. The results are consistent with a dominant negative mechanism for the deletion mutation. The Elovl4 knockout mouse is one of three complementary animal models that will help elucidate the disease mechanism.

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