Human Molecular Genetics Advance Access published online on January 5, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddl480
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Loss of functional ELOVL4 depletes very long-chain fatty acids (
C28) and the unique 
-O-acylceramides in skin leading to neonatal death
1 Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI- 48105 2 Department of Dermatology, School of Medicine, University of California San Francisco, and Veterans Administration Medical Center, San Francisco, CA-94121 3 Laboratory of Membrane Biochemistry and Biophysics, NIAAA, National Institutes of Health, Rockville, MD-20892 4 National Institute of Nutrition, Hyderabad, India 5 Department of Medicine Medical University of South Carolina, Charleston, SC-29425 6 Applied Biosystems, Framingham, MA-01701 7 Department of Dermatology, University of Michigan, Ann Arbor, MI- 48105 8 Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, CA-94143
* Address for correspondence: Radha Ayyagari, PhD. Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, 1000 Wall Street, Ann Arbor, MI 48105, Phone: 734-647-6345, Fax: 734-936-7231, Email: ayyagari{at}umich.edu
Received November 15, 2006; Revised December 28, 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), while electron microscopy revealed deficient epidermal lamellar body contents, and lack of normal stratum corneum 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 (VLFA) (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 
-O-acylceramides, that are key hydrophobic components of the extracellular lamellar membranes in mammalian stratum corneum. These findings demonstrate that ELOVL4 is required for generating VLFA critical for epidermal barrier function, and that the lack of epidermal -O-acylceramides is incompatible with survival in a desiccating environment.
$ These authors contributed equally to this work.
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