A rare missense mutation in a type 2 diabetes patient decreases the transcriptional activity of human sterol regulatory element binding protein-1

Abstract

Sterol regulatory element binding protein 1 (SREBP-1) transcription factors play a key role in energy homeostasis by regulating genes involved in both carbohydrate and lipid metabolism, and in adipocyte differentiation. The 5' end of the mRNA-encoding SREBP-1 exists in two forms, designated 1a and 1c. The divergence results from the use of two transcription start sites that produce two separate 5' exons, each of which is spliced to a common exon 2. Mutations in the sterol regulatory element binding protein gene (SREBF)-1 may contribute to insulin resistance states. However, the variants described to date do not affect the SREBP function. In this study, we investigated the functional consequences of a novel missense mutation common to both SREBP-1 isoforms identified in a Spanish type 2 diabetic patient (c.677C>T, SREBP-1a p.T226M; c.605C>T, SREBP-1c p.T202M). Using reporter gene analysis and electrophoretic mobility shift assays, we found that this variant impairs the transcriptional activity and reduces DNA binding ability despite its comparable protein stability to the wild-type SREBP-1. This decreased activity impairs the expression of known downstream targets, such as the LDL receptor and fatty acid synthase genes. Our findings suggest that the threonine residue and/or surrounding region play an important role in the SREBP-1 function.

Reciprocal regulation of the human sterol regulatory element binding protein (SREBP)‐1a promoter by Sp1 and EGR‐1 transcription factors

“…Protein analysis was carried out by Western blot as previously described [10] using antibodies to EGR‐1 (Santa Cruz Biotechnology, Santa Cruz, CA, USA).…”

SREBP-1c Transcription Factor and Lipid Homeostasis: Clinical Perspective

“…In all the studies described above, no functional data concerning the variants identified were provided. Vernia et al [90] have described the first SREBP-1 mutation found in a type 2 diabetic patient that modifies the function of the protein, diminishing its DNA binding efficiency and its ability to activate the transcription of target genes. Unfortunately, family data were not available for cohort studies and it is thus difficult to directly relate the observed mutation and the type 2 diabetes of the patient.…”