Two novel mutations in the lipoprotein lipase gene in a family with markedhypertriglyceridemia in heterozygous carriers: potential interaction with the polymorphic marker D1S104 on chromosome 1q21-q23

Two novel mutations in the lipoprotein lipase (LPL) gene are described in a n Austrian family: a splice site mutation in intron 1 (3 bp deletion of nuc leotides -2 to -4) which results in skipping of exon 2, and a missense muta tion in exon 5 which causes an asparagine for histidine substitution in cod on 183 and complete loss of enzyme activity. A 5-year-old boy who exhibited all the clinical features of primary hyperchylomicronemia was a compound h eterozygote for these two mutations. Nine other family members were investi gated: seven were heterozygotes for the splice site mutation, one was a het erozygote for the missense mutation, and one had two wild-type alleles of t he LPL gem, LPL activity in the post-heparin plasma of the heterozygotes wa s reduced to 49-79% of the mean observed in normal individuals. Two of the heterozygotes had extremely high plasma triglyceride levels; in three of th e other heterozylgotes the plasma triglycerides were also elevated. As plas ma triglycerides in carriers of one defective LPL allele can be normal or e levated, the heterozygotes of this family have been studied for a possible additional cause of the expression of hypertriglyceridemia in these subject s. Body mass index, insulin resistance, mutations in other candidate genes (Asn291Ser and Asp9Asn in the LPL gene, apoE isoforms, polymorphisms in the apoA-II gem and in the apoAI-CIII-AIV gene cluster, and in the IRS-I gene) could be ruled out as possible factors contributing to the expression of h ypertriglyceridemia in this family,A linkage analysis using the allelic mar ker DIS104 on chromosome 1q21-q23 suggested that a gene in this region coul d play a role in the expression of hypertriglyceridemia in the heterozygous carriers of this family, but the evidence was not sufficiently strong to p rove this assumption. Nevertheless, this polymorphic marker seems to be a g ood candidate for further studies. Two novel mutations in the lipoprotein l ipase gene in a family with marked hypertriglyceridemia in heterozygous car riers: potential interaction with the polymorphic marker DIS104 on chromoso me 1q21-q23.