Identification of a gene variant in the master regulator of lipid metabolism SREBP-1 in a family with a novel form of severe combined hypolipidemia

Objective: Alterations of lipid metabolism play a pivotal role in the development of atherosclerosis and its complications, today's major mortality risks. The predominant regulators controlling cholesterol- and fatty acids synthesis in liver are the sterol regulatory element-binding proteins (SREBPs), a family of transcription factors that were formerly identified as cholesterol sensor for LDLR gene expression. Variation of gene structure in these genes might therefore indicate a predisposition to develop complications like myocardial infarction and stroke. Methods: We investigated 190 unrelated German subjects, including 69 subjects with LDL-cholesterol < 55 mg/dl, for mutations in SREBP genes SREBF-1 and SREBF-2 by direct sequencing. The impact on SREBP functionality was analyzed by protein biochemical analyses, promoter reporter gene assays and gene expression studies. Results: A missense mutation in SREBF-1 (c.332 C > T; P111L) was identified in a subject with LDL-cholesterol < 5 mg/dl. Examination of the subject's family confirmed the mutation in two of three siblings. Detailed clinical evaluation of these subjects disclose a novel form of primary combined hypolipidemia only in SREBP-1a P111L carriers, characterized by low levels of apoB and apoA1, low triglyceride, LDL-cholesterol and HDL-cholesterol levels. Functional analyses indicated that the mutation abolishes phosphorylation of SREBP-1. As a consequence transcriptional activation of classical target genes, i.e. LDLR, HMG-CoAR, FAS, ABCA1, but also MTTP, was dramatically reduced. Conclusions: Phosphorylation of SREBP-1, the master regulator of genes for central rate limiting enzymes of cholesterol and lipid metabolism, appears to be a biological principle with clinical implications. (C) 2011 Published by Elsevier Ireland Ltd.