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Mutations in the SC4MOL gene encoding a novel methyl sterol oxidase cause autosomal recessive psoriasisiform dermatitis, microcephaly and developmental delay

Miao He¹, Lisa Kratz², Jushua Michel³, Abbe Vallejo³, Laura Ferris³, Richard Kelley², Jacqueline Hoover³, Michael Gibson³ & Gerard Vockley³

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1. Emory University, Department of Human Genetics, Atlanta, USA
2. The Kennedy Krieger Institute, Baltimore, MD, USA
3. University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

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Document Type:

Manuscript

Date:

Received 06 August 2008 13:32 UTC; Posted 07 August 2008

Subjects:

Genetics & Genomics, Immunology

Tags:

• gene
• skin
• Cholesterol
• psoriasis

Abstract:

Disorders of cholesterol biosynthesis have clinical manifestations involving skeleton, eyes, neurologic development, and skin. We describe a patient with congenital cataracts, developmental delay, microcephaly, and low serum cholesterol who developed severe psoriasiform dermatitis and arthralgias beginning at age 3. Her brain MRI indicatedminor gliosis. Quantitative sterol analysis of patient plasma and skin showed marked elevation of 4alpha-methyl- and 4, 4’-dimethylsterols, indicating a deficiency in the first step of sterol C4 demethylation in cholesterol biosynthesis. Molecular studies showed mutations in SC4MOL, a gene predicted to encode a sterol C4 methyl oxidase. Thus, our patient has a previously undescribed inborn error of cholesterol biosynthesis. Cellular studies with patient-derived fibroblasts showed higher mitotic rate than control cells in cholesterol-depleted medium, in which de novo cholesterol biosynthesis was increased with the accumulation of methylsterol. Immunologic analyses showed dysregulation of immune-related receptors in the patient and her father. Inhibition of sterol C4 methyl oxidase in human transformed lymphoblasts or in fresh leukocytes induced activation of cell cycle, and immune receptor dysregulation. These findings suggest that methylsterols influence mitotic capacity and immune function. SC4MOL is situated within the psoriasis susceptibility locus PSORS9, and is likely a genetic risk factor for common psoriasis.

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This document is licensed to the public under the Creative Commons Attribution 3.0 License

How to cite this document:

He, Miao, Kratz, Lisa, Michel, Jushua, Vallejo, Abbe, Ferris, Laura, Kelley, Richard, Hoover, Jacqueline, Gibson, Michael, and Vockley, Gerard. Mutations in the SC4MOL gene encoding a novel methyl sterol oxidase cause autosomal recessive psoriasisiform dermatitis, microcephaly and developmental delay. Available from Nature Precedings <http://hdl.handle.net/10101/npre.2008.2163.1> (2008)

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