Abstract
Individuals with hepatic lipase (HL) deficiency are often characterized by elevated levels of triglycerides (TGs) and cholesterol. The aim of the present study was to characterize the molecular defect leading to severe HL deficiency in a Québec-based kindred. In the proband and two of her brothers, the very low to undetectable HL activity resulted from compound heterozygosity for two rare HL gene mutations, a previously unknown missense mutation in exon 5 designated A174T and the previously reported T383M mutation in exon 8 of the HL gene. The mutation at codon 174 resulted in the substitution of alanine for threonine, a polar amino acid, in a highly conserved nonpolar region of the protein involved in the catalytic activity of the enzyme. The severe HL deficiency among the three related compound heterozygotes was associated with a marked TG enrichment of LDL and HDL particles. The two men with severe HL deficiency also presented with abdominal obesity, which appeared to amplify the impact of HL deficiency on plasma TG-rich lipoprotein levels. Our results demonstrated that HL deficiency in this Québec kindred is associated with an abnormal lipoprotein-lipid profile, which may vary considerably in the presence of secondary factors such as abdominal obesity.
Highlights
Individuals with hepatic lipase (HL) deficiency are often characterized by elevated levels of triglycerides (TGs) and cholesterol
We report a previously unknown missense mutation in exon 5 of the HL gene due to a G→A base change resulting in the change of an alanine for a threonine in codon 174 of the mature protein
This novel single nucleotide mutation resulting in the substitution of alanine for threonine at amino acid 174 was identified in the proband and her two younger brothers (Fig. 1)
Summary
Individuals with hepatic lipase (HL) deficiency are often characterized by elevated levels of triglycerides (TGs) and cholesterol. The determination of the role of HL in human lipoprotein metabolism has been facilitated by the identification of patients with HL deficiency This rare genetic disorder, which appears to be inherited as an autosomal recessive trait, has been identified in only five families to date [15,16,17,18,19]. One of the most consistent findings in the lipoprotein phenotype of HL-deficient subjects is an elevation of HDL2 cholesterol [21, 24, 25] and a marked TG enrichment of LDL and HDL particles [20, 22, 24]
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