Abstract
Two novel mutations in the lipoprotein lipase (LPL) gene are described in an Austrian family: a splice site mutation in intron 1 (3 bp deletion of nucleotides −2 to −4) which results in skipping of exon 2, and a missense mutation in exon 5 which causes an asparagine for histidine substitution in codon 183 and complete loss of enzyme activity. A 5-year-old boy who exhibited all the clinical features of primary hyperchylomicronemia was a compound heterozygote for these two mutations. Nine other family members were investigated: seven were heterozygotes for the splice site mutation, one was a heterozygote for the missense mutation, and one had two wild-type alleles of the LPL gene. LPL activity in the post-heparin plasma of the heterozygotes was reduced to 49–79% of the mean observed in normal individuals. Two of the heterozygotes had extremely high plasma triglyceride levels; in three of the other heterozygotes the plasma triglycerides were also elevated. As plasma triglycerides in carriers of one defective LPL allele can be normal or elevated, the heterozygotes of this family have been studied for a possible additional cause of the expression of hypertriglyceridemia in these subjects. Body mass index, insulin resistance, mutations in other candidate genes (Asn291Ser and Asp9Asn in the LPL gene, apoE isoforms, polymorphisms in the apoA-II gene and in the apoAI-CIII-AIV gene cluster, and in the IRS-1 gene) could be ruled out as possible factors contributing to the expression of hypertriglyceridemia in this family. A linkage analysis using the allelic marker D1S104 on chromosome 1q21–q23 suggested that a gene in this region could play a role in the expression of hypertriglyceridemia in the heterozygous carriers of this family, but the evidence was not sufficiently strong to prove this assumption. Nevertheless, this polymorphic marker seems to be a good candidate for further studies.—Hölzl, B., H. G. Kraft, H. Wiebusch, A. Sandhofer, J. Patsch, F. Sandhofer, and B. Paulweber. Two novel mutations in the lipoprotein lipase gene in a family with marked hypertriglyceridemia in heterozygous carriers: potential interaction with the polymorphic marker D1S104 on chromosome 1q21–q23. J. Lipid Res. 2000. 41: 734–741.
Highlights
Two novel mutations in the lipoprotein lipase (LPL) gene are described in an Austrian family: a splice site mutation in intron 1 (3 bp deletion of nucleotides ؊2 to ؊4) which results in skipping of exon 2, and a missense mutation in exon 5 which causes an asparagine for histidine substitution in codon 183 and complete loss of enzyme activity
Two novel mutations in the lipoprotein lipase gene are identified as the molecular basis of type I hyperlipemia in an Austrian family: a splice acceptor site mutation in intron 2 which results in skipping of exon 2, and a missense mutation in exon 5 which causes an asparagine for histidine substitution in codon 183 and a complete loss of lipolytic activity of the gene product
Three other carriers of this mutation showed an elevation of their triglyceride concentration (324, 257, 216 mg/dl), whereas two heterozygotes carrying the splice site mutation and one heterozygote with the missense mutation in exon 5 had normal plasma triglycerides
Summary
Two novel mutations in the lipoprotein lipase (LPL) gene are described in an Austrian family: a splice site mutation in intron 1 (3 bp deletion of nucleotides ؊2 to ؊4) which results in skipping of exon 2, and a missense mutation in exon 5 which causes an asparagine for histidine substitution in codon 183 and complete loss of enzyme activity. As plasma triglycerides in carriers of one defective LPL allele can be normal or elevated, the heterozygotes of this family have been studied for a possible additional cause of the expression of hypertriglyceridemia in these subjects. A linkage analysis using the allelic marker D1S104 on chromosome 1q21–q23 suggested that a gene in this region could play a role in the expression of hypertriglyceridemia in the heterozygous carriers of this family, but the evidence was not sufficiently strong to prove this assumption This polymorphic marker seems to be a good candidate for further studies.—Hölzl, B., H. Primary hyperchylomicronemia is a rare inherited metabolic disorder characterized by extremely high triglyceride levels due to accumulation of chylomicrons in the blood In patients with this disease, lipoprotein lipase (LPL) activity is absent or markedly decreased [1].
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