Homozygous missense mutation (G56R) in glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPI-HBP1) in two siblings with fasting chylomicronemia (MIM 144650)
Jian Wang
1
Robert A Hegele
0
1
0
Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute
,
406-100 Perth Drive, London, ON, N6A 5K8
,
Canada
1
Schulich School of Medicine and Dentistry, University of Western Ontario and Vascular Biology Research Group, Robarts Research Institute
,
London, Ontario, N6A 5K8
,
Canada
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.
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Background
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) [1]. Recently,
mice with induced deficiency in Gpihbp1 showed
compromised lipolysis leading to severe chylomicronemia, even
on a low-fat diet [2]. 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
Only one rare coding sequence variant in GPIHBP1 was
found among the 160 screened patients, namely G56R
(Figure 1A). This missense mutation was absent from the
genomes of 600 normolipidemic Caucasian control
subjects and 610 Caucasian patients with hyperlipidemia.
The mutated amino acid residue was evolutionarily
conserved (Figure 1B) and analysis with the PolyPhen
algorithm [3] indicated that the mutation was probably
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
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
AGG CTC CCT GGT GGC AGG AGC
5R3 5L4 5P5 5G6 5G7 5R8 5S9
AGG CTC CCT NGT GGGC AGG AGC
5R3 5L4 5P5 G5/6R 57 5R8 5S9
AGG CTC CCT CGT GGC AGG AGC
5R3 5L4 5 (...truncated)