A COMPOUND HETEROZYGOTE FOR LIPOPROTEIN-LIPASE DEFICIENCY, VAL(69)-]LEU AND GLY(188)-]GLU - CORRELATION BETWEEN IN-VITRO LPL ACTIVITY AND CLINICAL EXPRESSION

We analyzed the molecular defects in the lipoprotein lipase gene of a patient with type I hyperlipidemia suffering from recurrent pancreatit is, indicative for lipoprotein lipase deficiency. Postheparin lipoprot ein lipase activity in the patient was decreased by 70%. Direct genomi c sequencing revealed compound heterozygosity for two mutations: the w ell-known Gly(188)-->Glu and a new Val(69)-->Leu substitution. Val(69) is Situated in a conserved hydrophobic region of the lipoprotein lipa se protein, and the substitution with leucine gives rise to a 80% decr ease in specific catalytic activity, as supported by site-directed mut agenesis experiments, followed by expression in COS-cells. The combina tion of both defects in the lipoprotein lipase gene was incidently ass ociated with severe clinical expression of disease, and triglyceride l evels of more than 30 mmol/l were measured. In our patient, triglyceri de levels were 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 occurr ed only when conditions such as alcohol abuse or poor compliance to di et were present.