May 2007
Volume 48, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2007
Stargardt Like Macular Degeneration Gene ELOVL4 is Critical for Very Long Chain Fatty Acid Elongation & -Hydroxy Ceramide Formation
Author Affiliations & Notes
  • V. Vasireddy
    Univ of Michigan-Kellogg Eye Ctr, Ann Arbor, Michigan
    Dept. of Ophthalmology,
  • Y. Uchida
    Dermatology,
    Univ. of California San Francisco, San Francisco, California
  • N. Salem, Jr.
    Laboratory of Membrane Biochemistry & Biophysics, NIAAA, National Institutes of Health, Rockville, Maryland
  • S. Kim
    Laboratory of Membrane Biochemistry & Biophysics, NIAAA, National Institutes of Health, Rockville, Maryland
  • N. Mandal
    Univ of Michigan-Kellogg Eye Ctr, Ann Arbor, Michigan
    Ophthalmology,
  • R. Bodepudi
    Univ of Michigan-Kellogg Eye Ctr, Ann Arbor, Michigan
    Ophthalmology,
  • P. M. Elias
    Dermatology,
    Univ. of California San Francisco, San Francisco, California
  • W. M. Holleran
    Dermatology, Pharmaceutical Chemistry,
    Univ. of California San Francisco, San Francisco, California
  • R. Ayyagari
    Univ of Michigan-Kellogg Eye Ctr, Ann Arbor, Michigan
    Dept. of Ophthalmology,
  • Footnotes
    Commercial Relationships V. Vasireddy, None; Y. Uchida, None; N. Salem, None; S. Kim, None; N. Mandal, None; R. Bodepudi, None; P.M. Elias, None; W.M. Holleran, None; R. Ayyagari, None.
  • Footnotes
    Support NIH grants EY13198, NIH core grants to University of Michigan, Department of Ophthalmology and Visual Sciences (EY07003, EY07060), the Foundation Fighting Blindness
Investigative Ophthalmology & Visual Science May 2007, Vol.48, 2980. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      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.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
Abstract

Purpose:: 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

Methods:: 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.

Results:: 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.

Conclusions:: 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.

Keywords: retinal degenerations: hereditary • pathobiology • lipids 
×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×