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; Frederick E Domann

doi:10.1194/jlr.M300273-JLR200

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

Journal article

Open access

Peer reviewed

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

Journal of lipid research, Vol.44(12), pp.2311-2319

12/2003

DOI: 10.1194/jlr.M300273-JLR200

PMID: 12951357

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Abstract

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.

Fatty Acid Desaturases - genetics

Skin - cytology

Humans

RNA, Messenger - genetics

Rats

RNA Stability

RNA, Messenger - metabolism

Promoter Regions, Genetic - genetics

Sequence Homology, Nucleic Acid

Mutagenesis, Insertional - genetics

Regulatory Sequences, Nucleic Acid - genetics

Animals

Base Sequence

Fibroblasts

Linoleoyl-CoA Desaturase

Electrophoretic Mobility Shift Assay

Mice

Transcription, Genetic - genetics

Fatty Acid Desaturases - deficiency

3T3 Cells

Details

Title: Subtitle: A nucleotide insertion in the transcriptional regulatory region of FADS2 gives rise to human fatty acid delta-6-desaturase deficiency
Creators: Joseph O Nwankwo - Department of Biochemistry, University of Iowa, Iowa City, IA 52242, USA
Arthur A Spector
Frederick E Domann
Resource Type: Journal article
Publication Details: Journal of lipid research, Vol.44(12), pp.2311-2319
DOI: 10.1194/jlr.M300273-JLR200
PMID: 12951357
NLM abbreviation: J Lipid Res
ISSN: 0022-2275
eISSN: 1539-7262
Publisher: United States
Grant note: HL-49264 / NHLBI NIH HHS P01 CA66081 / NCI NIH HHS R01 L72845 / PHS HHS
Language: English
Date published: 12/2003
Academic Unit: Pathology; Surgery; Radiation Oncology; Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9984047683802771

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