title: Heterozygous hepatic lipase deficiency, due to two missense mutations R186H and L334F, in the HL gene.
abstract: Hepatic lipase (HL) is an endothelial enzyme involved in the metabolism of intermediate density lipoproteins (IDL) and high density lipoproteins (HDL) in plasma. In a Finnish pedigree consisting of 18 members belonging to three generations two missense mutations RI86H and L334F in exons 5 and 7 of the HL gene co-segregated with low post-heparin HL activity. Haplotype analysis of the HL gene in family members revealed a high degree of genetic variation and demonstrated that the two missense mutations reside on the same chromosome. In vitro site-directed mutagenesis and expression of the cDNA constructs in COS-1 cells revealed that the R186H mutation leads to a protein that is not secreted while the L334F mutation results in the production of a HL protein that is secreted but has only about 30% of wild type HL activity. Carriers of the mutated HL gene exhibited clearly reduced HL activity and mass in post-heparin plasma. Probably due to their heterozygous carrier status they had only moderate elevation of total triglycerides, IDL, and LDL-triglycerides. The LDL-particles were enriched in triglycerides and depleted of cholesterol. Also their HDL2- and HDL3-particles were enriched in triglycerides.
authors.affiliation: Department of Medicine, Helsinki University Hospital, Finland.
authors.forename: P
authors.initials: P
authors.lastname: Knudsen
authors.forename: M
authors.initials: M
authors.lastname: Antikainen
authors.forename: M
authors.initials: M
authors.lastname: Uusi-Oukari
authors.forename: S
authors.initials: S
authors.lastname: Ehnholm
authors.forename: S
authors.initials: S
authors.lastname: Lahdenperä
authors.forename: A
authors.initials: A
authors.lastname: Bensadoun
authors.forename: H
authors.initials: H
authors.lastname: Funke
authors.forename: H
authors.initials: H
authors.lastname: Wiebusch
authors.forename: G
authors.initials: G
authors.lastname: Assmann
authors.forename: M R
authors.initials: MR
authors.lastname: Taskinen
authors.forename: C
authors.initials: C
authors.lastname: Ehnholm
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000032:analysis; D005260:Female; D005796:Genes; D006493:Heparin / Q000494:pharmacology; D006579:Heterozygote; D006801:Humans; D008049:Lipase / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree
chemical_list: D008055:Lipids; D008074:Lipoproteins; D006493:Heparin; D004247:DNA; D008049:Lipase