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Journal of Lipid Research, Vol. 44, 2311-2319, December 2003
Copyright © 2003 by American Society for Biochemistry and Molecular Biology

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^1,,

^* Department of Biochemistry, University of Iowa, Iowa City, IA 52242
Department of Radiation Oncology, University of Iowa, Iowa City, IA 52242
The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242

¹ To whom correspondence should be addressed. e-mail: 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 with 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 with normal cells and published sequences. Promoter-reporter assays demonstrated a 6-fold decrease in promoter activity in the polymorphic variant FADS2 regulatory region compared with 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 FADS2 gene.

Abbreviations: C/EBP, CCAAT enhancer binding protein; DF, delta-6-desaturase deficient human skin fibroblasts; DHA, docosahexaenoic acid; FADS2, fatty acid delta-6-desaturase gene; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; NF, normal human skin fibroblasts; SCD, stearoyl-CoA-desaturase (delta-9-desaturase); SC5D, sterol C5-desaturase-like (delta-5-desaturase)

Supplementary key words fatty acid metabolism • polyunsaturated fatty acid • gene expression • insertion polymorphism • CCAAT enhancer binding protein

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