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

Vidyullatha Vasireddy, Yoshikazu Uchida, Norman Salem, Soo Yeon Kim, Nawajes Mandal, Geereddy Bhanuprakash Reddy, Ravi Bodepudi, Nathan L. Alderson, Johnie C. Brown, Hiroko Hama, Andrzej Dlugosz, Peter M. Elias, Walter M. Holleran, Radha Ayyagari

Research output: Contribution to journalArticle

150 Citations (Scopus)

Abstract

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 ω-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 ω-O-acylceramides is incompatible with survival in a desiccating environment.

Original languageEnglish (US)
Pages (from-to)471-482
Number of pages12
JournalHuman Molecular Genetics
Volume16
Issue number5
DOIs
StatePublished - Mar 1 2007
Externally publishedYes

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Fatty Acids
Cornea
Skin
Epidermis
Permeability
Glucosylceramides
Mutation
Membranes
Sequence Deletion
Ceramides
Nonesterified Fatty Acids
Base Pairing
Retina
Histology
Electron Microscopy
Carbon
Parturition
Lipids
Amino Acids
Perinatal Death

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Loss of functional ELOVL4 depletes very long-chain fatty acids (≥C28) and the unique ω-O-acylceramides in skin leading to neonatal death. / Vasireddy, Vidyullatha; Uchida, Yoshikazu; Salem, Norman; Kim, Soo Yeon; Mandal, Nawajes; Reddy, Geereddy Bhanuprakash; Bodepudi, Ravi; Alderson, Nathan L.; Brown, Johnie C.; Hama, Hiroko; Dlugosz, Andrzej; Elias, Peter M.; Holleran, Walter M.; Ayyagari, Radha.

In: Human Molecular Genetics, Vol. 16, No. 5, 01.03.2007, p. 471-482.

Research output: Contribution to journalArticle

Vasireddy, V, Uchida, Y, Salem, N, Kim, SY, Mandal, N, Reddy, GB, Bodepudi, R, Alderson, NL, Brown, JC, Hama, H, Dlugosz, A, Elias, PM, Holleran, WM & Ayyagari, R 2007, 'Loss of functional ELOVL4 depletes very long-chain fatty acids (≥C28) and the unique ω-O-acylceramides in skin leading to neonatal death', Human Molecular Genetics, vol. 16, no. 5, pp. 471-482. https://doi.org/10.1093/hmg/ddl480
Vasireddy, Vidyullatha ; Uchida, Yoshikazu ; Salem, Norman ; Kim, Soo Yeon ; Mandal, Nawajes ; Reddy, Geereddy Bhanuprakash ; Bodepudi, Ravi ; Alderson, Nathan L. ; Brown, Johnie C. ; Hama, Hiroko ; Dlugosz, Andrzej ; Elias, Peter M. ; Holleran, Walter M. ; Ayyagari, Radha. / Loss of functional ELOVL4 depletes very long-chain fatty acids (≥C28) and the unique ω-O-acylceramides in skin leading to neonatal death. In: Human Molecular Genetics. 2007 ; Vol. 16, No. 5. pp. 471-482.
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abstract = "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 ω-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 ω-O-acylceramides is incompatible with survival in a desiccating environment.",
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AU - Salem, Norman

AU - Kim, Soo Yeon

AU - Mandal, Nawajes

AU - Reddy, Geereddy Bhanuprakash

AU - Bodepudi, Ravi

AU - Alderson, Nathan L.

AU - Brown, Johnie C.

AU - Hama, Hiroko

AU - Dlugosz, Andrzej

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