title: A compound heterozygote for lipoprotein lipase deficiency, Val69-->Leu and Gly188-->Glu: correlation between in vitro LPL activity and clinical expression.
abstract: We analyzed the molecular defects in the lipoprotein lipase gene of a patient with type I hyperlipidemia suffering from recurrent pancreatitis, indicative for lipoprotein lipase deficiency. Postheparin lipoprotein lipase activity in the patient was decreased by 70%. Direct genomic sequencing revealed compound heterozygosity for two mutation: the well-known Gly188-->Glu and a new Val69-->Leu substitution. Val69 is situated in a conserved hydrophobic region of the lipoprotein lipase protein, and the substitution with leucine gives rise to a 80% decrease in specific catalytic activity, as supported by site-directed mutagenesis experiments, followed by expression in COS-cells. The combination of both defects in the lipoprotein lipase gene was incidentally associated with severe clinical expression of disease, and triglyceride levels of more than 30 mmol/l were measured. In our patient, triglyceride levels wer usually below 10 mmol/l. We, therefore, postulate that the residual LPL activity in our patient is usually sufficient to keep the triglyceride level within bounds and expression of disease occurred only when conditions such as alcohol abuse or poor compliance to diet were present.
authors.affiliation: Centre for Hemostasis, Thrombosis, Atherosclerosis, and Inflammation Research, University of Amsterdam, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Bruin
authors.forename: S
authors.initials: S
authors.lastname: Tuzgöl
authors.forename: W J
authors.initials: WJ
authors.lastname: Mulder
authors.forename: A E
authors.initials: AE
authors.lastname: van den Ende
authors.forename: H
authors.initials: H
authors.lastname: Jansen
authors.forename: M R
authors.initials: MR
authors.lastname: Hayden
authors.forename: J J
authors.initials: JJ
authors.lastname: Kastelein
mesh_terms: D000328:Adult; D001483:Base Sequence; D015139:Blotting, Southern; D004247:DNA / Q000032:analysis / Q000737:chemistry; D005971:Glutamates; D018698:Glutamic Acid; D005998:Glycine; D006579:Heterozygote; D006801:Humans; D007930:Leucine; D008071:Lipoprotein Lipase / Q000097:blood / Q000172:deficiency* / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D014633:Valine
chemical_list: D005971:Glutamates; D018698:Glutamic Acid; D004247:DNA; D008071:Lipoprotein Lipase; D007930:Leucine; D014633:Valine; D005998:Glycine