A novel GPIHBP1 mutation related to familial chylomicronemia syndrome: A series of cases

Lima, Josivan Gomes de; Nóbrega, Lúcia Helena Coelho; Bandeira, Flora Tamires Moura; Sousa, Anésio Mendes de; Macedo, Taisa Barreto Medeiros de Araujo; Nogueira, Ana Cláudia Cavalcante; Filho, Antonio Fernandes de Oliveira; Alves, Renato Jorge; Castelo, Maria Helane Costa Gurgel; Coelho, Fabiana Maria Silva; Maia, Rayana Elias; Lima, Debora Nobrega; Timóteo, Ana Rafaela de Souza; Campos, Julliane Tamara Araújo de Melo

doi:10.1016/j.atherosclerosis.2021.02.020

Cited by 14 publications

(12 citation statements)

References 43 publications

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“…Currently, a large amount of evidence supports that GPIHBP1 functions in triglyceride-rich lipoprotein (TRL) metabolism of human in unique and diverse ways ( 32 – 34 ). Recent studies have shown that LPL mislocalization as a result of GPIHBP1 deficiency may cause severe hyperlipidemia ( 13 , 35 ). Therefore, the importance of GPIHBP1 in lipolysis is being recognized more widely with more relevant research published.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that the defects directly related to LPL gene variants are also relevant to the majority of severe hyperlipidemia cases (3)(4)(5)(6). The rest 5% are the results of variants in other genes involving in LPL functioning, including APOC2 (encoding apolipoprotein CII, activator of LPL; OMIM #207750) (7,8), APOA5 (encoding apolipoprotein AV, activator of LPL; OMIM #144650) (9,10), LMF1 (encoding lipase maturation factor 1, a tissue factor triggering the secretion of functional LPL and hepatic lipase; OMIM #611761) (11,12), and GPIHBP1 (encoding glycosylphosphatidylinositol-anchored highdensity lipoprotein-binding protein 1, the molecular platform by which LPL is able to interact with TG-rich lipoproteins, apolipoprotein CII, and apolipoprotein AV on the endothelial surface of capillaries; OMIM #612757) (13,14). Meanwhile, there are also other variants to be identified (3), and all these variants may result in LPL malfunction.…”

Section: Introductionmentioning

confidence: 99%

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Case Report: Successful Management of a 29-Day-Old Infant With Severe Hyperlipidemia From a Novel Homozygous Variant of GPIHBP1 Gene

et al. 2022

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BackgroundSevere hyperlipidemia is characterized by markedly elevated blood triglyceride levels and severe early-onset cardiovascular diseases, pancreatitis, pancreatic necrosis or persistent multiple organ failure if left untreated. It is a rare autosomal recessive metabolic disorder originated from the variants of lipoprotein lipase gene, and previous studies have demonstrated that most cases with severe hyperlipidemia are closely related to the variants of some key genes for lipolysis, such as LPL, APOC2, APOA5, LMF1, and GPIHBP1. Meanwhile, other unidentified causes also exist and are equally worthy of attention.MethodsThe 29-day-old infant was diagnosed with severe hyperlipidemia, registering a plasma triglyceride level as high as 25.46 mmol/L. Whole exome sequencing was conducted to explore the possible pathogenic gene variants for this patient.ResultsThe infant was put on a low-fat diet combined with pharmacological therapy, which was successful in restraining the level of serum triglyceride and total cholesterol to a low to medium range during the follow-ups. The patient was found to be a rare novel homozygous duplication variant-c.45_48dupGCGG (Pro17Alafs*22) in GPIHBP1 gene-leading to a frameshift which failed to form the canonical termination codon TGA. The mutant messenger RNA should presumably produce a peptide consisting of 16 amino acids at the N-terminus, with 21 novel amino acids on the heels of the wild-type protein.ConclusionsOur study expands on the spectrum of GPIHBP1 variants and contributes to a more comprehensive understanding of the genetic diagnosis, genetic counseling, and multimodality therapy of families with severe hyperlipidemia. Our experience gained in this study is also contributory to a deeper insight into severe hyperlipidemia and highlights the importance of molecular genetic tests.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Case Report: Successful Management of a 29-Day-Old Infant With Severe Hyperlipidemia From a Novel Homozygous Variant of GPIHBP1 Gene

et al. 2022

View full text Add to dashboard Cite

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“…Currently, a large amount of evidence supports that GPIHBP1 functions in triglyceride-rich lipoprotein (TRL) metabolism of human in unique and diverse ways [23][24][25]. Recent studies have shown that LPL mislocalization as a result of GPIHBP1 de ciency may cause severe hyperlipidemia [13,26]. Therefore, the importance of GPIHBP1 in lipolysis is being recognized more widely with more relevant research published.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that the defects directly related to LPL gene variants are also relevant to the majority of severe hyperlipidemia cases [3][4][5][6]. The rest 5% are the results of variants in other genes involving in LPL functioning, including APOC2 (encoding apolipoprotein CII, activator of LPL; OMIM #207750) [7,8], APOA5 (encoding apolipoprotein AV, activator of LPL; OMIM #144650) [9,10], LMF1 (encoding lipase maturation factor 1, a tissue factor triggering the secretion of functional LPL and hepatic lipase; OMIM #611761) [11,12], and GPIHBP1 (encoding glycosylphosphatidylinositol-anchored highdensity lipoprotein-binding protein 1, the molecular platform by which LPL is able to interact with TG-rich lipoproteins, apolipoprotein CII, and apolipoprotein AV on the endothelial surface of capillaries; OMIM #612757) [13,14]. Meanwhile, there are also other variants to be identi ed [3], and all these variants may result in LPL malfunction.…”

Section: Introductionmentioning

confidence: 99%

Successful Management of a 29-Day-Old Infant with Severe Hyperlipidemia from a Novel Homozygous Variant of GPIHBP1 Gene

Liu

Wang

Zheng

et al. 2021

Preprint

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Background: Severe hyperlipidemia is characterized by markedly elevated blood triglyceride levels and severe early-onset cardiovascular diseases, pancreatitis, pancreatic necrosis or persistent multiple organ failure if left untreated. It is a rare autosomal recessive metabolic disorder originated from the variants of lipoprotein lipase gene, and previous studies have demonstrated that most cases with severe hyperlipidemia are closely related to the variants of some key genes for lipolysis, such as LPL, APOC2, APOA5, LMF1 and GPIHBP1. Meanwhile, other unidentified causes also exist and are equally worthy of attention.Methods: The 29-day-old infant was diagnosed with severe hyperlipidemia, registering a plasma triglyceride level as high as 25.46 mmol/L. Whole exome sequencing was conducted to explore the possible pathogenic gene variants for this patient.Results: The infant was put on a low-fat diet combined with pharmacological therapy, which was successful in restraining the level of serum triglyceride and total cholesterol to a low to medium range during the follow-ups. The patient was found to be a rare novel homozygous duplication variant—c.45_48dupGCGG (Pro17Alafs*22) in GPIHBP1 gene—leading to a frameshift which failed to form the canonical termination codon TGA. The mutant messenger RNA should presumably produce a peptide consisting of 16 amino acids at the N-terminus, with 21 novel amino acids on the heels of the wild-type protein.Conclusions: Our study expands on the spectrum of GPIHBP1 variants and contributes to a more comprehensive understanding of the genetic diagnosis, genetic counseling, and multimodality therapy of families with severe hyperlipidemia. Our experience gained in this study is also contributory to a deeper insight into severe hyperlipidemia and highlights the importance of molecular genetic tests.

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“…The proper folding of LU-domain proteins is generally sensitive to missense mutations of any of its plesiotypic cysteine residues or to deletion of its disulfide bonds (Figure 3B; Leth et al, 2019a,b). This sensitivity, combined with the high abundance of cysteine residues (10-15%), explains why the majority of disease-causing variants of GPIHBP1 affects plesiotypic cysteine residues (e.g., p.Cys 65 Tyr, p.Cys 65 Ser, p.Cys 68 Tyr, p.Cys 68 Gly, p.Cys 83 Arg, p.Cys 89 Phe) (Fong et al, 2016;Lima et al, 2021). In cell culture experiments, GPIHBP1 variants with missense mutations affecting cysteine residues give rise to multimerized GPIHBP1 molecules on the cell surface that do not bind LPL (Beigneux et al, 2009(Beigneux et al, , 2015.…”

Section: Disease-relevant Missense Variants In Gpihbp1mentioning

confidence: 99%

GPIHBP1 and ANGPTL4 Utilize Protein Disorder to Orchestrate Order in Plasma Triglyceride Metabolism and Regulate Compartmentalization of LPL Activity

Kristensen

Leth-Espensen

Kumari

et al. 2021

Front. Cell Dev. Biol.

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Intravascular processing of triglyceride-rich lipoproteins (TRLs) is crucial for delivery of dietary lipids fueling energy metabolism in heart and skeletal muscle and for storage in white adipose tissue. During the last decade, mechanisms underlying focal lipolytic processing of TRLs along the luminal surface of capillaries have been clarified by fresh insights into the functions of lipoprotein lipase (LPL); LPL’s dedicated transporter protein, glycosylphosphatidylinositol-anchored high density lipoprotein–binding protein 1 (GPIHBP1); and its endogenous inhibitors, angiopoietin-like (ANGPTL) proteins 3, 4, and 8. Key discoveries in LPL biology include solving the crystal structure of LPL, showing LPL is catalytically active as a monomer rather than as a homodimer, and that the borderline stability of LPL’s hydrolase domain is crucial for the regulation of LPL activity. Another key discovery was understanding how ANGPTL4 regulates LPL activity. The binding of ANGPTL4 to LPL sequences adjacent to the catalytic cavity triggers cooperative and sequential unfolding of LPL’s hydrolase domain resulting in irreversible collapse of the catalytic cavity and loss of LPL activity. Recent studies have highlighted the importance of the ANGPTL3–ANGPTL8 complex for endocrine regulation of LPL activity in oxidative organs (e.g., heart, skeletal muscle, brown adipose tissue), but the molecular mechanisms have not been fully defined. New insights have also been gained into LPL–GPIHBP1 interactions and how GPIHBP1 moves LPL to its site of action in the capillary lumen. GPIHBP1 is an atypical member of the LU (Ly6/uPAR) domain protein superfamily, containing an intrinsically disordered and highly acidic N-terminal extension and a disulfide bond–rich three-fingered LU domain. Both the disordered acidic domain and the folded LU domain are crucial for the stability and transport of LPL, and for modulating its susceptibility to ANGPTL4-mediated unfolding. This review focuses on recent advances in the biology and biochemistry of crucial proteins for intravascular lipolysis.

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A novel GPIHBP1 mutation related to familial chylomicronemia syndrome: A series of cases

Cited by 14 publications

References 43 publications

Case Report: Successful Management of a 29-Day-Old Infant With Severe Hyperlipidemia From a Novel Homozygous Variant of GPIHBP1 Gene

Case Report: Successful Management of a 29-Day-Old Infant With Severe Hyperlipidemia From a Novel Homozygous Variant of GPIHBP1 Gene

Successful Management of a 29-Day-Old Infant with Severe Hyperlipidemia from a Novel Homozygous Variant of GPIHBP1 Gene

GPIHBP1 and ANGPTL4 Utilize Protein Disorder to Orchestrate Order in Plasma Triglyceride Metabolism and Regulate Compartmentalization of LPL Activity

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