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.
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 Elovl4haploinsufficiency 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.
Authors: Md Nawajes A Mandal; Rajesh Ambasudhan; Paul W Wong; Philip J Gage; Paul A Sieving; Radha Ayyagari Journal: Genomics Date: 2004-04 Impact factor: 5.736
Authors: Pamela S Lagali; Jiafan Liu; Rajesh Ambasudhan; Laura E Kakuk; Steven L Bernstein; Gail M Seigel; Paul W Wong; Radha Ayyagari Journal: Invest Ophthalmol Vis Sci Date: 2003-07 Impact factor: 4.799
Authors: Vidyullatha Vasireddy; Yoshikazu Uchida; Norman Salem; Soo Yeon Kim; Md Nawajesh Ali Mandal; Geereddy Bhanuprakash Reddy; Ravi Bodepudi; Nathan L Alderson; Johnie C Brown; Hiroko Hama; Andrzej Dlugosz; Peter M Elias; Walter M Holleran; Radha Ayyagari Journal: Hum Mol Genet Date: 2007-01-05 Impact factor: 6.150
Authors: Mohammed A Aldahmesh; Jawahir Y Mohamed; Hisham S Alkuraya; Ishwar C Verma; Ratna D Puri; Ayodele A Alaiya; William B Rizzo; Fowzan S Alkuraya Journal: Am J Hum Genet Date: 2011-11-17 Impact factor: 11.025
Authors: Xi-Qin Ding; Arjun Thapa; Hongwei Ma; Jianhua Xu; Michael H Elliott; Karla K Rodgers; Marci L Smith; Jin-Shan Wang; Steven J Pittler; Vladimir J Kefalov Journal: J Biol Chem Date: 2016-02-18 Impact factor: 5.157