HETEROZYGOUS HEPATIC LIPASE DEFICIENCY, DUE TO 2 MISSENSE MUTATIONS R186H AND L334F, IN THE HL GENE

Hepatic lipase (HL) is an endothelial enzyme involved in the metabolis m of intermediate density lipoproteins (IDL) and high density lipoprot eins (HDL) in plasma. In a Finnish pedigree consisting of Is members b elonging to three generations two missense mutations RI86H and L334F i n 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 miss ense mutations reside on the same chromosome. In vitro site-directed m utagenesis and expression of the cDNA constructs in COS-I cells reveal ed that the R186H mutation leads to a protein that is not secreted whi le the L334F mutation results in the production of a HL protein that i s secreted but has only about 30% of wild type HL activity. Carriers o f the mutated HL gene exhibited clearly reduced HL activity and mass i n post-heparin plasma. Probably due to their heterozygous carrier stat us they had only moderate elevation of total triglycerides, IDL, and L DL-triglycerides. The LDL-particles were enriched in triglycerides and depleted of cholesterol. Also their HDL2- and HDL3-particles were enr iched in triglycerides. (C) 1997 Elsevier Science Ireland Ltd.