HGNC Approved Gene Symbol: GPIHBP1
Cytogenetic location: 8q24.3 Genomic coordinates (GRCh38) : 8:143,213,218-143,217,170 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q24.3 | Hyperlipoproteinemia, type 1D | 615947 | Autosomal recessive | 3 |
Dietary fats are packaged by the intestine into triglyceride-rich lipoproteins called chylomicrons. The triglycerides in chylomicrons are hydrolyzed by lipoprotein lipase (LPL; 609708) along the luminal surface of capillaries, mainly in heart, skeletal muscle, and adipose tissue. GPIHBP1 is a capillary endothelial cell protein that provides a platform for LPL-mediated processing of chylomicrons (Beigneux et al., 2007).
Ioka et al. (2003) cloned mouse Gpihbp1. The deduced 228-amino acid protein has an N-terminal signal sequence, followed by an acidic region with a cluster of aspartate and glutamate residues, an Ly6 (see 606038) motif, and a C-terminal hydrophobic region that resembles a glycosylphosphatidylinositol (GPI) anchor. EST database analysis detected a possible Gpihbp1 splice variant encoding a C-terminally truncated protein that was predicted to be soluble. Northern blot analysis detected Gpihbp1 expression in mouse heart, with weaker expression in lung and liver. No expression was detected in brain, kidney, skeletal muscle, spleen, and testis. In situ hybridization detected Gpihbp1 in Kupffer cells and sinusoidal endothelium of liver, in cardiac muscle cells, and in bronchial epithelium and alveolar macrophages in lung.
Using Northern blot analysis, Beigneux et al. (2007) found that mouse Gpihbp1 was highly expressed in adipose tissue and heart. Immunofluorescence microscopy revealed that Gpihbp1 was expressed exclusively in endothelial cells. Confocal microscopy revealed Gpihbp1 on the luminal face of capillaries in brown adipose tissue and heart. No Gpihbp1 was detected in capillaries of brain, which relies on glucose uptake rather than lipoprotein hydrolysis.
Using transfected Chinese hamster ovary (CHO) cells, Ioka et al. (2003) showed that mouse Gpihbp1 bound radiolabeled high density lipoprotein (HDL). Gpihbp1 selectively bound the lipid component of HDL, but not cholesterol or protein.
Beigneux et al. (2007) showed that transfection of mouse Gpihbp1 in CHO cells conferred the ability to bind LPL and chylomicrons. Binding of LPL to Gpihbp1 was eliminated by heparin, which releases LPL from endothelial cells, and cell surface Gpihbp1 was released by phospholipase C (see PLCG1; 172420).
Using cells grown on transwells, Davies et al. (2012) found that mouse Gpihbp1 could transport human LPL across rat heart endothelial cells in either the basolateral-to-apical direction or the apical-to-basolateral direction. Electron microscopy of rat and mouse cells revealed localization of Gpihbp1 and LPL in invaginations of the plasma membrane and in cytoplasmic vesicles. Inhibition of vesicular transport inhibited LPL internalization, whereas LPL internalization remained intact in mouse endothelial cells lacking caveolin-1 (CAV1; 601047).
Hartz (2009) mapped the GPIHBP1 gene to chromosome 8q24.3 based on an alignment of the GPIHBP1 sequence (GenBank AF088057) with the genomic sequence (build 36.1).
Wang and Hegele (2007) screened the coding regions of the GPIHBP1 gene in 160 unrelated adults with fasting chylomicronemia and plasma triglycerides greater than 10 mmol/L (615947), each of whom had normal sequence of the LPL (609708) and APOC2 (608083) genes, and identified 1 patient who was homozygous for a missense mutation (G56R; 612757.0001). Her affected brother was homozygous for the same mutation. Both sibs had recurrent pancreatitis.
Beigneux et al. (2009) screened 60 patients with chylomicronemia (plasma triglycerides, 4,464 +/- 3,366 mg/dL; postheparin plasma LPL mass and activity, 79.5 +/- 48.7 ng/mL and 59.9 +/- 63.9 mU/mL, respectively). The patients were identified within the Lipid Clinic of the Academic Medical Center Amsterdam. After excluding mutations in LPL, APOA5 (606368), and APOC2, Beigneux et al. (2009) amplified and sequenced the coding regions of GPIHBP1 and identified a homozygous missense mutation (Q115P; 612757.0002) in a 33-year-old male. The mutation did not affect the ability of GPIHBP1 to reach the cell surface, but it abrogated the ability to bind LPL or chylomicrons. Mouse Gpihbp1 with the corresponding mutation (Q114P) also could not bind Lpl. This mutation was subsequently reported in a second patient by Surendran et al. (2012).
Olivecrona et al. (2010) reported a family in which 3 sibs with chylomicronemia were compound heterozygous for 2 missense mutations in GPIHBP1 (C65S, 612757.0003 and C68G, 612757.0004). In transfection experiments in CHO cells, Olivecrona et al. (2010) showed that GPIHBP1 carrying either of these mutations could reach the cell surface but could not bind LPL.
Charriere et al. (2011) reported 2 probands with resistant hyperchylomicronemia, low LPL activity, and a history of acute pancreatitis who had mutations in the GPIHBP1 gene. One patient was homozygous for a G175R mutation (612757.0005); the other patient had a C89F mutation (612757.0006) on the paternal allele and a deletion of GPIHBP1 on the maternal allele (612757.0011). The C89F mutation disrupts the C65-C89 disulfide bond and causes major alteration of LPL binding, confirming the critical importance of the C65-C89 disulfide bond in GPIHBP1 structure and function. The C89F mutation was associated with a C14F signal peptide polymorphism on the same haplotype, and the authors suggested that it might potentiate the effects of the C89F mutation.
By whole-exome sequencing in a 5-week-old girl with severe hypertriglyceridemia, Gonzaga-Jauregui et al. (2014) identified compound heterozygous mutations in the GPIHBP1 gene: a missense mutation (T111P; 612757.0007) and a 17-bp deletion resulting in a frameshift (612757.0008).
In a patient with severe chylomicronemia, Franssen et al. (2010) identified a homozygous missense mutation in the GPIHBP1 gene (C65Y; 612757.0009). Transfection experiments in CHO cells showed that the mutant protein could reach the cell surface but could not bind LPL. When the patient was given heparin, only trace amounts of LPL entered the plasma. The C65Y mutation was also reported in an independent patient by Surendran et al. (2012).
In 3 sibs with chylomicronemia, Plengpanich et al. (2014) identified homozygosity for a missense mutation in the GPIHBP1 gene (S107C; 612757.0010). This extra cysteine resulted in the formation of disulfide-linked dimers and multimers on the cell surface, whereas wildtype GPIHBP1 is predominantly monomeric. Multimeric GPIHBP1 was unable to bind LPL in either cell-based or cell-free binding assays.
Beigneux et al. (2007) found that Gpihbp1 -/- mice had milky plasma with significantly increased triglyceride levels. Gpihbp1 -/- plasma showed a striking accumulation of chylomicrons, even when animals were fed a low-fat diet. Plasma triglyceride levels of Gpihbp1 +/- mice were indistinguishable from normal controls. Beigneux et al. (2007) concluded that GPIHBP1 plays a critical role in lipolytic processing of chylomicrons.
This variant is classified as a variant of unknown significance because its contribution to chylomicronemia has not been confirmed.
In a sister and brother with chylomicronemia and recurrent pancreatitis, Wang and Hegele (2007) identified a homozygous mutation in the GPIHBP1 gene, resulting in a gly56-to-arg (G56R) substitution at a highly conserved residue. The brother also had early coronary heart disease. Three members of the family who were heterozygous for the mutation had fasting mild hypertriglyceridemia. The mutation was not found in 600 control subjects or in 610 patients with hyperlipidemia.
In functional studies, Gin et al. (2007) demonstrated that both wildtype and mutant GPIHBP1-G56R localized at the cell surface and yielded signals of equal intensity. The G56R mutation had no discernible effect on the binding of lipoprotein lipase or chylomicrons.
Beigneux et al. (2009) screened 60 patients with severe hypertriglyceridemia (615947) and plasma triglycerides above the 95th percentile for age and gender. They identified homozygosity for a c.344A-C transversion in exon 4 of the GPIHBP1 gene, resulting in a gln115-to-pro (Q115P) substitution in the most highly conserved segment of the Ly6 motif, in a 33-year-old man with type I hyperlipoproteinemia since childhood. The mutation completely abrogated the ability of GPIHBP1 to bind LPL. The same homozygous mutation was identified in 1 of 86 patients with severe hypertriglyceridemia screened by Surendran et al. (2012).
In 3 Swedish sibs with severe chylomicronemia (615947), Olivecrona et al. (2010) identified compound heterozygosity for mutations in exon 3 of the GPIHBP1 gene: a G-to-C transversion resulting in a cys65-to-ser (C65S) substitution, and a G-to-T transversion resulting in a cys68-to-gly (C68G; 612757.0004) substitution. Both mutations occurred in the highly conserved Ly6 domain. The asymptomatic and normolipemic parents were each heterozygous for one of the mutations, neither of which was found in 50 randomly selected healthy Swedish controls. The mutant GPIHBP1 proteins reached the surface of transfected CHO cells but were defective in their ability to bind LPL. Hamosh (2014) noted that neither variant was detected in the Exome Variant Server database.
For discussion of the cys68-to-gly (C68G) mutation in the GPIHBP1 gene that was found in compound heterozygous state in sibs with severe chylomicronemia (615947) by Olivecrona et al. (2010), see 612757.0003.
In a 35-year-old man with severe chylomicronemia (615947), Charriere et al. (2011) identified homozygosity for a G-to-C substitution in exon 4 of the GPIHBP1 gene, resulting in a gly175-to-arg (G175R) substitution in the C-terminal domain of the protein. The mutation altered the transfer of GPIHBP1 at the cell surface and reduced the ability of GPIHBP1 to bind LPL to just above 50% of wildtype levels. The mutation was not found in 220 normolipemic controls. Hamosh (2014) noted that the G175R mutation (rs145844329), was seen with a frequency of 27 in 12,970 alleles in the Exome Variant Server database but was not seen in homozygosity.
In a child with severe chylomicronemia (615947), Charriere et al. (2011) identified compound heterozygous mutations in the GPIHBP1 gene: a G-to-T change in exon 3 resulting in a cys89-to-phe (C89F) substitution in the Ly6 domain on the paternal allele, and a deletion of GPIHBP1 (612757.0011) on the maternal allele. The C89F mutation was associated with a C14F (rs11538389) substitution, which is a signal peptide polymorphism, on the same allele. In CHO cells, C14F reduced expression of GPIHBP1 at the cell surface, but the C89F mutation was responsible for a drastic LPL-binding defect to GPIHBP1. The authors suggested that the C14F polymorphism may potentiate the effect of C89F. The C89F substitution was not found in 220 normolipemic controls. Hamosh (2014) noted that C14F was detected in homozygosity in approximately 1% of samples in the Exome Variant Server database; C89F was absent from the database.
By whole-exome sequencing in a 5-week-old Hispanic girl with severe hypertriglyceridemia (615947), Gonzaga-Jauregui et al. (2014) identified compound heterozygous mutations in exon 4 of the GPIHBP1 gene: a c.331A-C transversion, resulting in a thr111-to-pro (T111P) substitution, and a 17-bp deletion (c.413_429del) resulting in a frameshift at val138 (612757.0008). Both mutations occur in the Ly6 domain of the protein. Hamosh (2014) noted that neither mutation was found in the Exome Variant Server database.
For discussion of the 17-bp deletion (c.413_429del) in the GPIHBP1 gene that was found in compound heterozygous state in a patient with severe chylomicronemia (615947) by Gonzaga-Jauregui et al. (2014), see 612757.0007.
In a 3-year-old boy with chylomicronemia (615947), Franssen et al. (2010) identified homozygosity for a 194G-A transition in exon 3 of the GPIHBP1 gene, resulting in a cys65-to-tyr (C65Y) substitution in the Ly6 domain of the protein. The mutant protein was able to reach the cell surface but could not bind to LPL. The same homozygous mutation was identified in an unrelated patient with chylomicronemia by Surendran et al. (2012). Hamosh (2014) noted that the C65Y mutation was not found in the Exome Variant Server database.
In 3 sibs with severe hypertriglyceridemia (615947), Plengpanich et al. (2014) identified homozygosity for a 320C-G transversion in the GPIHPB1 gene, resulting in a ser107-to-cys (S107C) substitution in the Ly6 domain of the protein. The mutation resulted in a gain of function and multimerization of GPIHBP1, precluding LPL binding. Hamosh (2014) noted that the S107C mutation was not present in the Exome Variant Server database.
For discussion of the deletion of GPIHBP1 that was found in compound heterozygous state in a patient with severe chylomicronemia (615947) by Charriere et al. (2011), see 612757.0006.
Beigneux, A. P., Davies, B. S. J., Gin, P., Weinstein, M. M., Farber, E., Qiao, X., Peale, F., Bunting, S., Walzem, R. L., Wong, J. S., Blaner, W. S., Ding, Z.-M., Melford, K., Wongsiriroj, N., Shu, X., de Sauvage, F., Ryan, R. O., Fong, L. G., Bensadoun, A., Young, S. G. Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 plays a critical role in the lipolytic processing of chylomicrons. Cell Metab. 5: 279-291, 2007. [PubMed: 17403372] [Full Text: https://doi.org/10.1016/j.cmet.2007.02.002]
Beigneux, A. P., Franssen, R., Bensadoun, A., Gin, P., Melford, K., Peter, J., Walzem, R. L., Weinstein, M. M., Davies, B. S. J., Kuivenhoven, J. A., Kastelein, J. J. P., Fong, L. G., Dallinga-Thie, G. M., Young, S. G. Chylomicronemia with a mutant GPIHBP1 (Q115P) that cannot bind lipoprotein lipase. Arterioscler. Thromb. Vasc. Biol. 29: 956-962, 2009. [PubMed: 19304573] [Full Text: https://doi.org/10.1161/ATVBAHA.109.186577]
Charriere, S., Peretti, N., Bernard, S., Di Filippo, M., Sassolas, A., Merlin, M., Delay, M., Debard, C., Lefai, E., Lachaux, A., Moulin, P., Marcais, C. GPIHBP1 C89F neomutation and hydrophobic C-terminal domain G175R mutation in two pedigrees with severe hyperchylomicronemia. J. Clin. Endocr. Metab. 96: E1675-E1679, 2011. Note: Electronic Article. [PubMed: 21816778] [Full Text: https://doi.org/10.1210/jc.2011-1444]
Davies, B. S. J., Goulbourne, C. N., Barnes, R. H., II, Turlo, K. A., Gin, P., Vaughan, S., Vaux, D. J., Bensadoun, A., Beigneux, A. P., Fong, L. G., Young, S. G. Assessing mechanisms of GPIHBP1 and lipoprotein lipase movement across endothelial cells. J. Lipid Res. 53: 2690-2697, 2012. [PubMed: 23008484] [Full Text: https://doi.org/10.1194/jlr.M031559]
Franssen, R., Young, S. G., Peelman, F., Hertecant, J., Sierts, J. A., Schimmel, A. W. M., Bensadoun, A., Kastelein, J. J. P., Fong, L. G., Dallinga-Thie, G. M., Beigneux, A. P. Chylomicronemia with low postheparin lipoprotein lipase levels in the setting of GPIHBP1 defects. Circ. Cardiovasc. Genet. 3: 169-178, 2010. [PubMed: 20124439] [Full Text: https://doi.org/10.1161/CIRCGENETICS.109.908905]
Gin, P., Beigneux, A. P., Davies, B., Young, M. F., Ryan, R. O., Bensadoun, A., Fong, L. G., Young, S. G. Normal binding of lipoprotein lipase, chylomicrons, and apo-AV to GPIHBP1 containing a G56R amino acid substitution. Biochem. Biophys. Acta 1771: 1464-1468, 2007. [PubMed: 17997385] [Full Text: https://doi.org/10.1016/j.bbalip.2007.10.005]
Gonzaga-Jauregui, C., Mir, S., Penney, S., Jhangiani, S., Midgen, C., Finegold, M., Muzny, D. M., Wang, M., Bacino, C. A., Gibbs, R. A., Lupski, J. R., Kellermayer, R., Hanchard, N. A. Whole-exome sequencing reveals GPIHBP1 mutations in infantile colitis with severe hypertriglyceridemia. J. Pediat. Gastroent. Nutr. 59: 17-21, 2014. [PubMed: 24614124] [Full Text: https://doi.org/10.1097/MPG.0000000000000363]
Hamosh, A. Personal Communication. Baltimore, Md. 7/15/2014.
Hartz, P. A. Personal Communication. Baltimore, Md. 4/23/2009.
Ioka, R. X., Kang, M.-J., Kamiyama, S., Kim, D.-H., Magoori, K., Kamataki, A., Ito, Y., Takei, Y. A., Sasaki, M., Suzuki, T., Sasano, H., Takahashi, S., Sakai, J., Fujino, T., Yamamoto, T. T. Expression cloning and characterization of a novel glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein, GPI-HBP1. J. Biol. Chem. 278: 7344-7349, 2003. [PubMed: 12496272] [Full Text: https://doi.org/10.1074/jbc.M211932200]
Olivecrona, G., Ehrenborg, E., Semb, H., Makoveichuk, E., Lindberg, A., Hayden, M. R., Gin, P., Davies, B. S. J., Weinstein, M. M., Fong, L. G., Beigneux, A. P., Young, S. G., Olivecrona, T., Hernell, O. Mutation of conserved cysteines in the Ly6 domain of GPIHBP1 in familial chylomicronemia. J. Lipid Res. 51: 1535-1545, 2010. [PubMed: 20026666] [Full Text: https://doi.org/10.1194/jlr.M002717]
Plengpanich, W., Young, S. G., Khovidhunkit, W., Bensadoun, A., Karnman, H., Ploug, M., Gardsvoll, H., Leung, C. S., Adeyo, O., Larsson, M., Muanpetch, S., Charoen, S., Fong, L. G., Niramitmahapanya, S., Beigneux, A. P. Multimerization of glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) and familial chylomicronemia from a serine-to-cysteine substitution in GPIHBP1 Ly6 domain. J. Biol. Chem. 289: 19491-19499, 2014. [PubMed: 24847059] [Full Text: https://doi.org/10.1074/jbc.M114.558528]
Surendran, R. P., Visser, M. E., Heemelaar, S., Wang, J., Peter, J., Defesche, J. C., Kuivenhoven, J. A., Hosseini, M., Peterfy, M., Kastelein, J. J. P., Johansen, C. T., Hegele, R. A., Stroes, E. S. G., Dallinga-Thie, G. M. Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients with severe hypertriglyceridaemia. J. Intern. Med. 272: 185-196, 2012. [PubMed: 22239554] [Full Text: https://doi.org/10.1111/j.1365-2796.2012.02516.x]
Wang, J., Hegele, R. A. Homozygous missense mutation (G56R) in glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPI-HBP1) in two siblings with fasting chylomicronemia (MIM 144650). Lipids Health Dis. 6: 23, 2007. Note: Electronic Article. [PubMed: 17883852] [Full Text: https://doi.org/10.1186/1476-511X-6-23]