Homozygous missense mutation (G56R) in glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPI-HBP1) in two siblings with fasting chylomicronemia (MIM 144650)

Abstract

Background: Mice with a deleted Gpihbp1 gene encoding glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPI-HBP1) develop severe chylomicronemia. We screened the coding regions of the human homologue--GPIHBP1--from the genomic DNA of 160 unrelated adults with fasting chylomicronemia and plasma triglycerides >10 mmol/L, each of whom had normal sequence of the LPL and APOC2 genes.

Results: One patient with severe type 5 hyperlipoproteinemia (MIM 144650), fasting chylomicronemia and relapsing pancreatitis resistant to standard therapy was found to be homozygous for a novel GPIHBP1 missense variant, namely G56R. This mutation was absent from the genomes of 600 control subjects and 610 patients with hyperlipidemia. The GPIHBP1 G56 residue has been conserved throughout evolution and the G56R mutation was predicted to have compromised function. Her homozygous brother also had refractory chylomicronemia and relapsing pancreatitis together with early coronary heart disease. G56R heterozygotes in the family had fasting mild hypertriglyceridemia.

Conclusion: Thus, a very rare GPIHBP1 missense mutation appears to be associated with severe hypertriglyceridemia and chylomicronemia.

Figure 1

Molecular genetic studies of GPIHBP1. A) DNA sequence analysis of GPIHBP1 exon 2 from genomic DNA of a normolipidemic subject (upper tracing), a G56R heterozygote (middle tracing) and the homozygote proband (lower tracing). For each tracing, normal nucleotide sequence is shown in the top line of letters, with single letter amino acid codes and codon numbers beneath. The position of the mutated nucleotide is indicated by the arrow. B) Evolutionary conservation of human GPIHBP1 G56 in primates and rodents; the single letter amino acid codes and peptide position for the homologous region from each species are shown. C) Nuclear family of the proband with severe type V hyperlipoproteinemia and fasting chylomicronemia. The proband (identification [ID] number II-3) and her older affected brother (ID II-1) are indicated with solid symbols. Genotype-proven heterozygotes are shown with half-solid symbols. Patient age and plasma concentrations of total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), all in millimoles per litre (mM), and of apolipoprotein (apo) A-I and B, in grams per litre (g/L), are shown. ND means the value could not be determined. A documented history of hospitalization for pancreatitis and coronary heart disease (CHD) are shown. Genotypes of the GBPHBP1 exon 2 G56R mutation and of common APOE isoforms are shown.