- Open Access
Homozygous missense mutation (G56R) in glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPI-HBP1) in two siblings with fasting chylomicronemia (MIM 144650)
© Wang and Hegele; licensee BioMed Central Ltd. 2007
- Received: 11 July 2007
- Accepted: 20 September 2007
- Published: 20 September 2007
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.
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.
Thus, a very rare GPIHBP1 missense mutation appears to be associated with severe hypertriglyceridemia and chylomicronemia.
- G56R Mutation
- Plasma Triglyceride Concentration
- Severe Hypertriglyceridemia
- Unrelated Adult
- APOC2 Gene
Glycosylphosphatidylinositol (GPI)-anchored high-density lipoprotein (HDL)-binding protein 1 (GPIHBP1) was identified by expression cloning as a cell surface protein that bound high-density lipoprotein (HDL) . Recently, mice with induced deficiency in Gpihbp1 showed compromised lipolysis leading to severe chylomicronemia, even on a low-fat diet . GPIHBP1 appears to provide a critical platform for the binding of both lipoprotein lipase (LPL) and chylomicrons [1, 2]. Since no human mutations in GPIHBP1 have yet been reported, we screened the genomic DNA of 160 unrelated adults with fasting chylomicronemia to search for coding sequence mutations in this gene.
Demographics of study sample
From a tertiary referral lipid clinic, we evaluated 160 patients (33% female, 35% with diabetes) who had fasting chylomicronemia on at least one occasion. Age, body mass index, untreated fasting plasma cholesterol and triglycerides (mean ± standard deviation [SD]) were, respectively, 50.5 ± 13.8 years, 30.2 ± 4.8 kg/m2, 11.9 ± 6.0 mmol/L and 31.1 ± 25.0 mmol/L. All subjects consented to DNA analysis. No coding sequence mutations were found in LPL and APOC2 genes encoding, respectively, lipoprotein lipase and apolipoprotein (apo) C-II.
Characterization of family with GPIHBP1 mutation
The proband, a homozygote for GPIHBP1 G56R, had relapsing pancreatitis beginning at age 22 and was documented on numerous occasions to refractory fasting chylomicronemia, even with fat restriction. She had no thyroid, renal or hepatic disease and was not diabetic. She was not obese and consumed no alcohol. Her older brother had a similar biochemical profile, with a history of relapsing pancreatitis requiring hospitalization, refractory to medical treatment since age 25. At age 45 he required 3-vessel coronary artery bypass graft surgery for unstable angina symptoms that began at age 44 (Figure 1C).
Both patients had normal activities of lipoprotein and hepatic lipases in post-heparin plasma, indicating that ex vivo lipolytic activity was not compromised. Both parents were long-deceased. Although consanguinity was not documented, it was possible since both parents were born in the same village. Three heterozygotes in this pedigree each had plasma triglyceride concentration in the top 5th percentile for age and sex, but no history of pancreatic or cardiovascular disease. Further, the proband's untreated son had combined hyperlipidemia, with approximately equimolar elevations of plasma total cholesterol and triglycerides, which together with an APOE E2/E2 genotype were highly suggestive of type 3 hyperlipoproteinemia (dysbetalipoproteinemia). Both patients have had a variable response to oral fibrate therapy, with a somewhat better response to restriction of fat intake to 20% of calories and to omega-3 fatty acids, although long term compliance has been an issue. Plasma triglyceride concentration was never <10 mmol/L in either patient over since their diagnosis.
The recent characterization of a focal role for Gpihbp1 in murine triglyceride metabolism was a significant development in the lipoprotein field . Our genetic findings suggest that GPIHBP1 might also have an important role in human triglyceride metabolism, albeit only one missense mutation in GPIHBP1 – G56R – was found among 160 patients with an analogous phenotype to mice with a deleted Gpihbp1 gene, namely severe type 5 hyperlipoproteinemia, fasting chylomicronemia and a normal coding sequence of LPL and APOC2 genes. The G56R mutation altered a highly conserved residue and functional compromise was predicted. The mutation was associated in homozygotes with severe, refractory hypertriglyceridemia. In heterozygotes, the mutation was associated with mild to moderate hypertriglyceridemia, and very likely with type 3 hyperlipoproteinemia in a subject who was also homozygous for APOE E2/E2. Furthermore, the G56R mutation was absent from large numbers of normolipidemic control subjects and also from a large number of patients referred to a tertiary clinic for management of a wide range of hyperlipidemia phenotypes.
The association of this coding sequence variant with severe type 5 hyperlipoproteinemia with chylomicronemia, its absence from normolipidemic subjects together with other evidence for its likely pathogenicity appears to link the GPIHBP1 gene with severe human metabolic phenotypes. The fact that this was the only mutation from hundreds of screened subjects with an appropriate disease phenotype indicates that mutations in this gene are not likely to be a major cause of severe hypertriglyceridemia.
Genomic DNA analysis
Amplification primers for GPIHBP1 coding sequence
annealing temperature (°C)
fragment size (base pairs)
5'-CCT TCA TCC CAC TTA CCG CAG C
5'-GCC AGC TTC CAT CCA TGC TGC
5'-ATG CTT GCC CAG AGC AGG TGT C
5'-GCC TGC TGG CTT CCA TCA CAC
5'-AGG CTA GGC TTT GGG AGC ACA G
5'-CTG CAG AGC CAC CTC AGA GAC
5'-CTG GAT CGC CCA AGA CAC TCC
This work was supported by operating grants from the Canadian Institutes of Health Research (MT14030), the Heart and Stroke Foundation of Ontario, and Genome Canada through the Ontario Genomics Institute. RAH is a Career Investigator of the Heart and Stroke Foundation of Ontario and holds the Edith Schulich Vinet Canada Research Chair (Tier I) in Human Genetics and the Jacob J. Wolfe Distinguished Medical Research Chair.
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