ABCMdb

ABCA1 p.Pro87Leu

Predicted by SNAP2:	A: N (57%), C: D (63%), D: D (75%), E: D (59%), F: D (71%), G: D (59%), H: N (53%), I: D (66%), K: N (53%), L: N (53%), M: D (66%), N: N (66%), Q: N (72%), R: N (72%), S: N (57%), T: N (57%), V: N (57%), W: D (75%), Y: D (66%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, Q: D, R: N, S: D, T: D, V: D, W: D, Y: D,

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Publications
[hide] Identification of a gene variant in the master reg... Atherosclerosis. 2011 Sep;218(1):134-43. Epub 2011 May 18. Kotzka J, Knebel B, Janssen OE, Schaefer JR, Soufi M, Jacob S, Nitzgen U, Muller-Wieland D
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.
Atherosclerosis. 2011 Sep;218(1):134-43. Epub 2011 May 18., [PMID:21645898]

Abstract [show]
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.

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185 In a previous report describing screening of the N-terminal exons of SREBP-1c in 85 subjects with severe insulin resistance and 47 controls a heterozygous P87L mutation was detected in a single affected subject, which corresponds to the mutation we found using SREBP-1a numbering [24]. Login to comment
212 The corresponding SREBP-1 P87L of isoform SREBP-1c does not affect DNA binding [24]. Login to comment