title: The lipoprotein lipase (LPL) S447X gain of function variant involves increased mRNA translation.
abstract: OBJECTIVE
  A common gain-of-function LPL variant, LPLS447X, has favorable clinical features and involves a C→G base change at nucleotide 1595 of the LPL cDNA, along with a haplotype, which includes other non-coding SNPs. The mechanism for the LPL gain-in-function is not clear. LPL translation is regulated by epinephrine by an RNA-protein complex, consisting of PKA subunits and an A kinase anchoring protein (AKAP), which targets the 3'UTR.
  
  
  METHODS
  To examine LPL translation of the LPLS447X variant, in vitro translation of LPL mRNA constructs was studied in the presence of cytoplasmic extracts from 3T3-F442A adipocytes treated with/without epinephrine.
  
  
  RESULTS
  When the C→G base change at nucleotide 1595 was introduced, LPL mRNA was less susceptible to inhibition by the adipocyte extract. Similarly, a lessened susceptibility to translation inhibition occurred when the complete haplotype was constructed in the full-length 3.6 kb LPL mRNA, when an irrelevant coding sequence was introduced into the LPL mRNA construct, and in response to the use of components of the RNA binding complex (PKA C and R subunits, and KH region of AKAP149).
  
  
  CONCLUSIONS
  These studies suggest that the LPLS447X gain of function may be due to the base change in the LPL mRNA resulting in a decreased susceptibility to translational inhibition.
authors.affiliation: The Central Arkansas Veterans Healthcare System and the Department of Medicine, Division of Endocrinology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States.
authors.forename: Gouri
authors.initials: G
authors.lastname: Ranganathan
authors.forename: Resat
authors.initials: R
authors.lastname: Unal
authors.forename: Irina D
authors.initials: ID
authors.lastname: Pokrovskaya
authors.forename: Preeti
authors.initials: P
authors.lastname: Tripathi
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.forename: Mark O
authors.initials: MO
authors.lastname: Goodarzi
authors.forename: Philip A
authors.initials: PA
authors.lastname: Kern
mesh_terms: D020413:3' Untranslated Regions; D016475:3T3 Cells; D054758:A Kinase Anchor Proteins / Q000378:metabolism; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004837:Epinephrine / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006239:Haplotypes; D006801:Humans; D008071:Lipoprotein Lipase / Q000096:biosynthesis* / Q000235:genetics*; D051379:Mice; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism*; D011817:Rabbits; D012156:Reticulocytes / Q000187:drug effects / Q000201:enzymology*; D013347:Subcellular Fractions
chemical_list: D020413:3' Untranslated Regions; D054758:A Kinase Anchor Proteins; D012333:RNA, Messenger; D017868:Cyclic AMP-Dependent Protein Kinases; C548261:LPL protein, human; D008071:Lipoprotein Lipase; D004837:Epinephrine