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Human Molecular Genetics Advance Access originally published online on January 5, 2007
Human Molecular Genetics 2007 16(5):471-482; doi:10.1093/hmg/ddl480
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Published by Oxford University Press 2007.
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact: journals.permissions@oxfordjournals.org

Loss of functional ELOVL4 depletes very long-chain fatty acids (≥C28) and the unique {omega}-O-acylceramides in skin leading to neonatal death

Vidyullatha Vasireddy1,{dagger}, Yoshikazu Uchida2,{dagger}, Norman Salem, Jr3, Soo Yeon Kim3, Md Nawajesh Ali Mandal1, Geereddy Bhanuprakash Reddy4, Ravi Bodepudi1, Nathan L. Alderson5, Johnie C. Brown6, Hiroko Hama5, Andrzej Dlugosz7, Peter M. Elias2, Walter M. Holleran2,8 and Radha Ayyagari1,*

1 Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48105, USA, 2 Department of Dermatology, School of Medicine, University of California, San Francisco, and Veterans Administration Medical Center, San Francisco, CA 94121, USA, 3 Laboratory of Membrane Biochemistry and Biophysics, NIAAA, National Institutes of Health, Bethesda, MD 20892, USA, 4 National Institute of Nutrition, Hyderabad, India, 5 Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA, 6 Applied Biosystems, Framingham, MA 01701, USA, 7 Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA and 8 Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, CA 94143, USA

* To whom correspondence should be addressed at: Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, 1000 Wall Street, Ann Arbor, MI 48105, USA. Tel: +1 7346476345; Fax: +1 7349367231; Email: ayyagari{at}umich.edu

Received November 15, 2006; Revised December 22, 2006; Accepted December 28, 2006

Mutations in elongation of very long-chain fatty acid-4 (ELOVL4) are associated with autosomal dominant Stargardt-like macular degeneration (STGD3), with a five base-pair (5 bp) deletion mutation resulting in the loss of 51 carboxy-terminal amino acids and truncation of the protein. In addition to the retina, Elovl4 is expressed in a limited number of mammalian tissues, including skin, with unknown function(s). We generated a knock-in mouse model with the 5-bp deletion in the Elovl4 gene. As anticipated, mice carrying this mutation in the heterozygous state (Elovl4+/del) exhibit progressive photoreceptor degeneration. Unexpectedly, homozygous mice (Elovl4del/del) display scaly, wrinkled skin, have severely compromised epidermal permeability barrier function, and die within a few hours after birth. Histopathological evaluation of the Elovl4del/del pups revealed no apparent abnormality(ies) in vital internal organs. However, skin histology showed an abnormally-compacted outer epidermis [stratum corneum (SC)], while electron microscopy revealed deficient epidermal lamellar body contents, and lack of normal SC lamellar membranes that are essential for permeability barrier function. Lipid analyses of epidermis from Elovl4del/del mice revealed a global decrease in very long-chain fatty acids (VLFAs) (i.e., carbon chain ≥C28) in both the ceramide/glucosylceramide and the free fatty-acid fractions. Strikingly, Elovl4del/del skin was devoid of the epidermal-unique {omega}-O-acylceramides, that are key hydrophobic components of the extracellular lamellar membranes in mammalian SC. These findings demonstrate that ELOVL4 is required for generating VLFA critical for epidermal barrier function, and that the lack of epidermal {omega}-O-acylceramides is incompatible with survival in a desiccating environment.

{dagger} These authors contributed equally to this work.


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