Lipoprotein lipase (LPL) catalyzes the hydrolysis of the core triacylglycerols of plasma very low density lipoproteins (VLDL) and chylomicrons (Brunzell, 1995). It thus controls a crucial step in the metabolism of triglycerides of exogenous and endogenous origin.
Inherited LPL deficiency is clinically expressed as chylomicronemia, hepatosplenomegaly , and recurrent episodes of pancreatitis. Although deleterious mutations have been identified in all parts of the LPL gene, a frequent cause of inherited LPL-deficiency is point mutations changing codons located in close vicinity to the catalytic center of the enzyme.
We have analyzed a 17-year-old girl and her family of north German descent. She presented with chylomicronemia and was lacking post heparin plasma LPL activity (0 pmoVml/hr normal controls: 9.3 t 2.3 pmoVmVhr). Her plasma HDL-cholesterol concentration was reduced to 20% of normal. Both parents (father, I1,l; 2.58 pmoVmVhr; mother, 142; 2.94 pmoVml/hr), her brother (111,3; 2.31 pmoYmVhr) and sister (111,2; 2.23 pmoVmVhr) exhibited half-normal post-heparin plasma LPL activities, whereas her grandmother (1,2) showed normal activity at 7.11 pmoVmVhr. The coding region, including the intron-exon boundaries of the LPL gene, was analysed by direct polymerase chain reaction (PCR)-based sequencing.
Gene analysis of the index patient (III,l) revealed a heterozygous A-to-G transition in codon 163 (Glu163GIy; GAG -+ GGG), and a heterozygous G-to-A transition in codon 188 (Gly188Glu; GGG + GAG). Family analysis showed heterozygosity for the Glu163Gly mutation in her sister (II,2) and her father (11,l). The patient's mother (II,2) and brother (I1,3) were identified as Gly188Glu heterozygotes (data reviewed but not shown) and the grandmother (I,2) showed wild-type sequence in all LPL codons.
The mutation in codon 188 is known to produce a nonfunctional LPL allele and has previously been shown to cause chylomicronemia in patients from different ancestries (Monsalve et al., 1992;Emi et al., 1990;Paulweber et al., 1991). By contrast, the Glu163Gly mutation in exon 5 of the LPL gene has not previously been observed. This mutation lies within the highly conserved central homology region in close proximity to the catalytic site of LPL (Emmerich et al., 1990). The impaired lipolytic activity and chylomicronemia observed in our patient thus appears to be the result of the compound heterozygosity for the Glu188Glu and Glu163Gly mutations.