Expression and regulation of a low-density lipoprotein receptor exon 12 splice variant

I. Fang Ling, Rangaraj K. Gopalra, James F. Simpson, Steven Estus

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

As low-density lipoprotein receptor (LDLR) contributes to cholesterol and amyloid beta homeostasis, insights into LDLR regulation may facilitate our understanding of cardiovascular disease and Alzheimer's disease. Previously, we identified LDLR isoforms that lacked exon 12 or exons 11-12 and that are predicted to encode soluble, dominant negative, LDLR. Moreover, these isoforms were associated with rs688, an exon 12 polymorphism that was associated with LDL-cholesterol and Alzheimer's disease risk. In this study, we present evidence that although the truncated LDLR isoforms are translated in vitro, they represent < 0.1% of CSF proteins. As these LDLR isoforms likely represent a loss of mRNAencoding functional LDLR, we then focused upon identifying intron-exon boundary and exonic splicing enhancer elements critical to splicing. Exon 12 inclusion is enhanced by altering the 5' splice site in intron 12 towards a consensus splice donor sequence, consistent with its being a weak 5' splice site. Additionally, of the nine evolutionarily conserved putative splicing enhancer regions within exon 12, two regions that flank rs688 were critical to exon 12 inclusion. Overall, these results suggest that LDLR splice variants represent a loss of mRNA encoding functional LDLR and provide insights into the regulatory elements critical for LDLR exon 12 splicing.

Original languageEnglish
Pages (from-to)614-624
Number of pages11
JournalJournal of Neurochemistry
Volume115
Issue number3
DOIs
StatePublished - Nov 2010

Funding

FundersFunder number
National Institute on AgingR01AG026147

    Keywords

    • Alzheimer's disease
    • Cholesterol
    • Low-density lipoprotein receptor
    • RNA splicing
    • Splicing regulatory element

    ASJC Scopus subject areas

    • Biochemistry
    • Cellular and Molecular Neuroscience

    Fingerprint

    Dive into the research topics of 'Expression and regulation of a low-density lipoprotein receptor exon 12 splice variant'. Together they form a unique fingerprint.

    Cite this