HIGH-FREQUENCY OF MUTATIONS IN THE HUMAN LIPOPROTEIN-LIPASE GENE IN PREGNANCY-INDUCED CHYLOMICRONEMIA - POSSIBLE ASSOCIATION WITH APOLIPOPROTEIN E2 ISOFORM

Partial deficiency in lipolysis usually results in only mild disturban ces of lipid levels. However, when this is associated with impairment of the uptake of remnant particles and increased production of triglyc eride-rich lipoproteins stimulated by environmental factors such as du ring normal pregnancy, chylomicronemia may ensue. We have previously r eported a patient who had approximately 12% of normal LPL activity and developed severe chylomicronemia during pregnancy (Ma et al. 1993. J. Clin. Invest. 91: 1953-1958). Here we report four new patients with p regnancy-induced chylomicronemia. In the nonpregnant state, these pati ents had mild to modest elevation of triglyceride levels ranging from 80 to 623 mg/dl (0.9-7.0 mmol/l) but during the third trimester they b ecame severely chylomicro-nemic with triglyceride levels ranging from 2314 to 14596 mg/dl (26 to 164 mmol/l). Three of these four patients h ad partial lipoprotein lipase (LPL) deficiency. The molecular characte rization of the LPL gene in these three patients with partial LPL defi ciency revealed four novel unpublished mutations. Patient #1 is a comp ound heterozygote for Leu252Arg and Ala261Thr mutations which are asso ciated with 25% of normal LPL activity. In addition, she has an apoE3/ 2 genotype. Patient #2 is a heterozygote for a Asn291Ser substitution with 69% of LPL activity and also has an apoE3/2 genotype, while patie nt #3 is a heterozygote for a Trp382Stop mutation with 54% of normal L PL activity and has an apoE4/2 genotype. The fourth patient (#4) with pregnancy-induced chylomicronemia does not have LPL deficiency and has an apoE3/3 genotype. The previously reported patient (#5) who had 12% of normal LPL activity due to homozygosity for a Ser172Cys mutation a lso has an E3/3 genotype. Our data suggest that mutations in the LPL g ene that cause partial LPL deficiency might be a frequent factor in th e pathogenesis of pregnancy-induced chylomicronemia.