title: 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.
abstract: 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 <55mg/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 <5mg/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.
authors.affiliation: Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center at Heinrich-Heine-University Duesseldorf, Leibniz Center for Diabetes Research, Aufm Hennekamp 65, 40225 Duesseldorf, Germany.
authors.forename: Jorg
authors.initials: J
authors.lastname: Kotzka
authors.forename: Birgit
authors.initials: B
authors.lastname: Knebel
authors.forename: Onno E
authors.initials: OE
authors.lastname: Janssen
authors.forename: J R
authors.initials: JR
authors.lastname: Schaefer
authors.forename: M
authors.initials: M
authors.lastname: Soufi
authors.forename: Sylvia
authors.initials: S
authors.lastname: Jacob
authors.forename: Ulrike
authors.initials: U
authors.lastname: Nitzgen
authors.forename: Dirk
authors.initials: D
authors.lastname: Muller-Wieland
mesh_terms: D000328:Adult; D002784:Cholesterol / Q000378:metabolism; D008078:Cholesterol, LDL / Q000378:metabolism; D005192:Family Health; D005260:Female; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D014644:Genetic Variation; D056945:Hep G2 Cells; D006801:Humans; D007009:Hypolipoproteinemias / Q000235:genetics*; D050356:Lipid Metabolism; D008297:Male; D008856:Microscopy, Fluorescence / Q000379:methods; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D017422:Sequence Analysis, DNA; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics
chemical_list: D008078:Cholesterol, LDL; C497390:SREBF2 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol