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A more recent version of this article appeared on December 1, 2003

Papers In Press, published online ahead of print September 1, 2003
J. Lipid Res., doi:10.1194/jlr.M300273-JLR200
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Submitted on June 20, 2003
Revised on August 14, 2003
Accepted on August 21, 2003

A nucleotide insertion in the transcriptional regulatory region of FADS2 gives rise to human fatty acid delta-6-desaturase deficiency

Joseph O. Nwankwo, Arthur A. Spector, and Frederick E. Domann

Radiation Oncology/Free Radical & Radiation Biology, The University of Iowa, Iowa City, IA 52242

Corresponding Author: frederick-domann{at}uiowa.edu

Fatty acid delta-6-desaturase (FADS2) is the rate-limiting enzyme in mammalian synthesis of long-chain polyunsaturated fatty acids. We investigated the molecular mechanism of FADS2 deficiency in skin fibroblasts from a patient deficient in this enzyme. Expression analyses demonstrated an 80 to 90% decrease in the steady state level of FADS2 mRNA in patient-derived cells compared to normal controls that was consistent with previous metabolic biochemical studies. In vitro transcription assays indicated an 80% decrease in the rate of transcriptional initiation in patient-derived cells, thus implicating transcriptional regulation as the mechanism for the decreased transcript levels. Sequence analysis of the 5’ end of the gene revealed the insertion of a thymidine between positions –941 and –942 upstream of the translation start site in patient-derived cells compared to normal cells and published sequences. Promoter-reporter assays demonstrated a six-fold decrease in promoter activity in the polymorphic variant FADS2 regulatory region compared to the normal gene, confirming the functional relevance of the insertion mutation to the decreased expression of the gene in the patient-derived cells. These findings indicate that fatty acid delta 6-desaturase deficiency and decreased FADS2 transcription are caused by a nucleotide insertion in the transcriptional regulatory region of the human gene FADS2 gene.


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