OR05-3 Cutaneous Lipid Abnormalities In C7orf58 Knockout Mice Reveal A Critical Role For C7orf58 In Epidermal Lipid Homeostasis And The Late Steps Of Cholesterol Biosynthesis

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR05-Lipids: Regulation & Mechanism of Disease
Basic/Clinical
Saturday, June 15, 2013: 11:30 AM-1:00 PM
Presentation Start Time: 12:00 PM
Room 133 (Moscone Center)
Jun Zhu*1 and Farid F Chehab2
1University of Califonia, San Francisco, CA, 2Univ of California, San Francisco, CA
We recently identified that the C7orf58 gene (also called CPED1) was disrupted by a chromosome translocation in an obese female with mental retardation and coarse features. To gain insights into the pathophysiology of this novel gene, we generated whole body knockout mice for the C7orf58 mouse homolog A430107O13Rik. On an inbred C57BL/6J genetic background, homozygous disruption of C7orf58 resulted in early embryonic lethality. However, heterozygous knockout mice were viable and normal, but approximately 20% of them display by 7 days of age, ichthyosis, alopecia and a severely compromised skin barrier function. Moreover, they display peripheral lipoatrophy and die invariably by 2-3 weeks of age. On the mixed 129-C57BL/6J genetic background, homozygosity for the null allele also results in embryonic lethality and a similar proportion of heterozygous knockout mice exhibit the same features as those on the C57BL/6J background. In addition, they develop kyphosis and survive for about 5 months. Histological skin analysis from heterozygous knockout mice with ichthyosis of both strains uncovered extensive keratinization of the surface epithelium and the epithelium lining the hair follicles. In the dermis, markedly decreased or absence of adipocytes was replaced by a proliferative epidermis. Also, electron microscopy revealed the presence of multiple abnormal lamellar bodies in the epidermis. Analyses of epidermal and dermal lipids from knockout mice with ichthyosis of both genetic strains revealed prominent accumulation only in the epidermis, of an unknown lipid that we unveiled by mass spectrometry to consist of 5alpha-cholesta-8,14-dien-3beta-ol, an intermediary sterol synthesized during the late steps of cholesterol biosynthesis. Furthermore, saturated very long chain fatty acids (22:0, 24:0, 26:0) and their respective conjugated ceramides were 4-10 fold higher in knockout than control mice. The likely role of C7orf58 in the distant cholesterol biosynthesis pathway is consistent with bioinformatics studies, proposing that it consists of a hydrolase/esterase. Taken together, our studies demonstrate that perturbed epidermal lipid biosynthesis associated with packaging of abnormal lipids into lamellar bodies result in the secretion of detrimental lipids to the stratum corneum, resulting in ichthyosis and its sequelae. Thus, the susceptibility of the epidermis to a systemic reduction of C7orf58 levels supports a critical role for C7orf58 in epidermal lipid homeostasis.

Nothing to Disclose: JZ, FFC

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