Journal of Lipid Research, Vol 35, 438-445, Copyright © 1994 by Lipid Research, Inc.
A compound heterozygote for lipoprotein lipase deficiency, Val69-->Leu and Gly188-->Glu: correlation between in vitro LPL activity and clinical expression
T Bruin, S Tuzgol, WJ Mulder, AE van den Ende, H Jansen, MR Hayden and JJ Kastelein
Centre for Hemostasis, Thrombosis, Atherosclerosis, and Inflammation Research, University of Amsterdam, The Netherlands.
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.
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