title: Splice-site mutations in atherosclerosis candidate genes: relating individual information to phenotype.
abstract: BACKGROUND
  Nucleotide variants in several genes for lipid and methionine metabolism influence the risk of premature atherosclerosis. Ten percent of single nucleotide substitutions in these genes involve mRNA splice sites. The effects of some of these changes on splicing and on phenotypic severity are not inherently obvious.
  
  
  RESULTS
  Using an information theory-based model, we measured the individual information content (R(i), in bits) of splice sites adjacent to 289 mutations (including 31 splice-site mutations) in the atherosclerosis candidate genes APOAII, APOB, APOCII, APOE, CBS, CETP, LCAT, LIPA, LDLR, and LPL. The predictions of information analysis were then corroborated by published mRNA analyses. The R(i) values of mutant sites were consistent with either complete (n=17) or partial (n=8) inactivation of these sites. Seven mutations were predicted to activate cryptic splice sites. Predicted inactive mutant sites were associated with either "average" or "severe" dyslipidemia and commensurate reductions in protein levels or activity, whereas mutations expected to exhibit residual splicing had average or "mild" effects on lipid and protein expression.
  
  
  CONCLUSIONS
  Information analysis of splice-junction variants in atherosclerosis candidate genes distinguishes inactive from leaky splice sites and identifies activated cryptic sites. Predicted changes in splicing were related to phenotypic severity.
authors.affiliation: Department of Cardiology, University Hospital Eppendorf, Hamburg, Germany.
authors.forename: Y
authors.initials: Y
authors.lastname: von Kodolitsch
authors.forename: R E
authors.initials: RE
authors.lastname: Pyeritz
authors.forename: P K
authors.initials: PK
authors.lastname: Rogan
mesh_terms: D019943:Amino Acid Substitution; D001161:Arteriosclerosis / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D005786:Gene Expression Regulation; D005796:Genes; D020022:Genetic Predisposition to Disease; D006801:Humans; D006949:Hyperlipidemias / Q000150:complications / Q000235:genetics; D007257:Information Theory; D050356:Lipid Metabolism; D008715:Methionine / Q000378:metabolism; D008957:Models, Genetic; D010641:Phenotype; D017354:Point Mutation; D014176:Protein Biosynthesis; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism; D012307:Risk Factors; D012720:Severity of Illness Index
chemical_list: D012333:RNA, Messenger; D008715:Methionine