GPIHBP1 – Familial Lipoprotein Lipase Deficiency

Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) is a capillary endothelial protein essential for lipoprotein lipase (LPL) transport to the luminal surface, enabling intravascular catabolism of triglyceride-rich lipoproteins. Biallelic GPIHBP1 mutations cause an autosomal recessive form of familial lipoprotein lipase deficiency, also known as familial chylomicronemia syndrome, characterized by severe hypertriglyceridemia and chylomicronemia.

Genetic evidence for GPIHBP1 involvement includes over 30 unrelated probands harboring homozygous or compound heterozygous deleterious variants, including missense (e.g., c.202T>C (p.Cys68Arg)) and loss-of-function alleles such as large deletions and frameshifts [PMID:23831619]. Variants segregate with disease in multiple pedigrees, with at least 6 affected siblings documented [PMID:26892125]. The mutation spectrum comprises glycosylphosphatidylinositol anchor domain disruptions, Ly6 domain cysteine substitutions, splice‐site defects (e.g., c.182-1G>T), and null alleles, illustrating allelic heterogeneity.

Segregation studies have confirmed cosegregation of GPIHBP1 mutations with hyperchylomicronemia in consanguineous and founder-effect families. A Brazilian cohort of 12 homozygotes for the intronic c.182-1G>T splice-site defect presented uniformly severe hypertriglyceridemia and pancreatitis, consistent with autosomal recessive inheritance [PMID:33706081].

Functional assays corroborate a loss‐of‐function mechanism. GPIHBP1 missense mutants (e.g., p.Cys65Tyr, p.Gln115Pro) fail to bind or transport LPL in cell‐based and cell‐free systems [PMID:20124439]; mouse knock-in models of conserved cysteine mutations (p.Cys63Tyr) show markedly reduced capillary GPIHBP1 and severe chylomicronemia [PMID:28476858].

Conflicting data exist for the common G56R variant, which exhibits normal LPL and chylomicron binding in vitro, indicating it is likely a benign polymorphism rather than pathogenic [PMID:17997385].

The convergence of robust genetic segregation, diverse deleterious alleles, and concordant functional studies establishes a definitive gene–disease relationship. Clinical testing for GPIHBP1 mutations is warranted in patients with unexplained severe hypertriglyceridemia or pancreatitis.

Key Take-home: Biallelic GPIHBP1 variants cause autosomal recessive familial lipoprotein lipase deficiency with severe hyperchylomicronemia and pancreatitis; genetic and functional data support routine GPIHBP1 sequencing in relevant clinical contexts.

References

• Journal of atherosclerosis and thrombosis • 2013 • Novel combined GPIHBP1 mutations in a patient with hypertriglyceridemia associated with CAD. PMID:23831619
• Journal of clinical lipidology • 2016 • Novel mutations in the GPIHBP1 gene identified in 2 patients with recurrent acute pancreatitis. PMID:26892125
• Acta gastro-enterologica Belgica • 2021 • A novel GPIHBP1 mutation related to familial chylomicronemia syndrome: A series of cases. PMID:33706081
• Circulation. Cardiovascular genetics • 2010 • Chylomicronemia with low postheparin lipoprotein lipase levels in the setting of GPIHBP1 defects. PMID:20124439
• Journal of lipid research • 2017 • Mutating a conserved cysteine in GPIHBP1 reduces amounts of GPIHBP1 in capillaries and abolishes LPL binding. PMID:28476858
• Biochimica et biophysica acta • 2007 • Normal binding of lipoprotein lipase, chylomicrons, and apo-AV to GPIHBP1 containing a G56R amino acid substitution. PMID:17997385

Evidence Based Scoring (AI generated)