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V. Vasireddy, Y. Uchida, N. Salem, Jr., S. Kim, N. Mandal, R. Bodepudi, P. M. Elias, W. M. Holleran, R. Ayyagari; Stargardt Like Macular Degeneration Gene ELOVL4 is Critical for Very Long Chain Fatty Acid Elongation & -Hydroxy Ceramide Formation. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2980.
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Mutations in ELOVL4, including a 5-bp deletion are involved in autosomal dominant Stargardt-like macular degeneration (STGD3). ELOVL4, predicted to participate in fatty acid (FA) chain elongation, was found to be expressed in retina, skin and brain. We generated a Elovl4 5-bp deletion knock-in mouse model and established that heterozygous mice develop retinal degeneration similar to the STGD3 phenotype. Here we report the consequences of the homozygous Elovl4 5-bp deletion mutation (E_mut del/del), revealing a critical role for ELOVL4 in FA elongation & sphingolipid metabolism
The phenotype of and histopathology of vital organs were evaluated in newborn control & E_mut del/del animals. Cutaneous structural abnormalities were analyzed by evaluating morphology and ultrastructure. FA & sphingolipid content were determined in control and E_mut del/del epidermis to elucidate the role of ELOVL4 in FA chain elongation.
E_mut del/del pups displayed scaly, wrinkled skin and died within a few hours after birth. Epidermal barrier function in these pups was abnormal. Histopathological evaluation of vital organs showed an abnormal epidermis (stratum corneum), while electron microscopy revealed significant abnormalities in lamellar bodies which primarily contain the precursors of epidermal lipids. Analyses of the lipid profile of E_mut del/del mice epidermis showed a significant decrease in very long chain fatty acids (VLFA) (i.e., carbon chain ≥C28) and total loss of epidermal-specific ω-O-acyl ceramides.
These studies reveal: (a) lack of functional ELOVL4 leads to neonatal lethality; (b) ELOVL4 is required for generating VLFA and the ω-O-acyl ceramides that are critical for establishing epidermal barrier function; and (c) in addition to retina, ELOVL4 has a critical role in other tissues. These observations enhance our understanding of the mechanism underlying photoreceptor degeneration due to ELOVL4 gene involvement and its role in FA elongation.
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