title: A novel amino acid substitution (His183-->Gln) in exon 5 of the lipoprotein lipase gene results in loss of catalytic activity: phenotypic expression of the mutant gene in a heterozygous state.
abstract: We have identified a hitherto unrecognized mutation of the lipoprotein lipase gene (LPL) in a Finnish family with Russian and Swiss ancestors. A single base pair substitution of a guanine for cytosine in codon 183 of exon 5 of the LPL gene results in a change of histidine to glutamine in the mature enzyme protein. Expression of a mutant cDNA construct in COS cells resulted in secretion of inactive LPL enzyme protein confirming the functional significance of the mutation. The proband, a 50-year-old female and her two daughters were all heterozygous for the His183-->Gln mutation. Clinically, the proband was characterized by variable and occasionally severe hypertriglyceridemia, obesity, hypertension, coronary heart disease and non-insulin-dependent diabetes mellitus. The daughters, aged 24 and 19 years, were also obese but had milder hypertriglyceridemia. In conclusion, we have identified a novel LPL mutation that results in the synthesis of an inactive enzyme protein. Although the assessment of a causative link between the mutation and hyperlipidemia awaits further studies, our data suggest that heterozygosity for a functional defect of LPL should be considered in patients presenting with the metabolic dyslipidemic syndrome, "syndrome-X."
authors.affiliation: National Public Health Institute, University of Helsinki, Finland.
authors.forename: H
authors.initials: H
authors.lastname: Tenkanen
authors.forename: M R
authors.initials: MR
authors.lastname: Taskinen
authors.forename: M
authors.initials: M
authors.lastname: Antikainen
authors.forename: I
authors.initials: I
authors.lastname: Ulmanen
authors.forename: K
authors.initials: K
authors.lastname: Kontula
authors.forename: C
authors.initials: C
authors.lastname: Ehnholm
mesh_terms: D000596:Amino Acids / Q000737:chemistry* / Q000502:physiology; D001483:Base Sequence; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000235:genetics; D005091:Exons; D005260:Female; D015870:Gene Expression; D006579:Heterozygote; D006801:Humans; D015228:Hypertriglyceridemia / Q000201:enzymology* / Q000235:genetics; D008055:Lipids / Q000097:blood; D008071:Lipoprotein Lipase / Q000235:genetics* / Q000502:physiology; D008074:Lipoproteins / Q000097:blood; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics / Q000502:physiology; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic
chemical_list: D000596:Amino Acids; D018076:DNA, Complementary; D008055:Lipids; D008074:Lipoproteins; D008071:Lipoprotein Lipase