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[PMID]:28402248
[Au] Autor:Beigneux AP; Miyashita K; Ploug M; Blom DJ; Ai M; Linton MF; Khovidhunkit W; Dufour R; Garg A; McMahon MA; Pullinger CR; Sandoval NP; Hu X; Allan CM; Larsson M; Machida T; Murakami M; Reue K; Tontonoz P; Goldberg IJ; Moulin P; Charrière S; Fong LG; Nakajima K; Young SG
[Ad] Endereço:From the Departments of Medicine (A.P.B., M.A.M., N.P.S., X.H., C.M.A., M.L., L.G.F., S.G.Y.), Rheumatology (M.A.M.), Human Genetics (K.R., S.G.Y.), and Pathology and Laboratory Medicine (P.T.), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, and the Cardiovascul
[Ti] Título:Autoantibodies against GPIHBP1 as a Cause of Hypertriglyceridemia.
[So] Source:N Engl J Med;376(17):1647-1658, 2017 04 27.
[Is] ISSN:1533-4406
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: A protein that is expressed on capillary endothelial cells, called GPIHBP1 (glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1), binds lipoprotein lipase and shuttles it to its site of action in the capillary lumen. A deficiency in GPIHBP1 prevents lipoprotein lipase from reaching the capillary lumen. Patients with GPIHBP1 deficiency have low plasma levels of lipoprotein lipase, impaired intravascular hydrolysis of triglycerides, and severe hypertriglyceridemia (chylomicronemia). During the characterization of a monoclonal antibody-based immunoassay for GPIHBP1, we encountered two plasma samples (both from patients with chylomicronemia) that contained an interfering substance that made it impossible to measure GPIHBP1. That finding raised the possibility that those samples might contain GPIHBP1 autoantibodies. METHODS: Using a combination of immunoassays, Western blot analyses, and immunocytochemical studies, we tested the two plasma samples (as well as samples from other patients with chylomicronemia) for the presence of GPIHBP1 autoantibodies. We also tested the ability of GPIHBP1 autoantibodies to block the binding of lipoprotein lipase to GPIHBP1. RESULTS: We identified GPIHBP1 autoantibodies in six patients with chylomicronemia and found that these autoantibodies blocked the binding of lipoprotein lipase to GPIHBP1. As in patients with GPIHBP1 deficiency, those with GPIHBP1 autoantibodies had low plasma levels of lipoprotein lipase. Three of the six patients had systemic lupus erythematosus. One of these patients who had GPIHBP1 autoantibodies delivered a baby with plasma containing maternal GPIHBP1 autoantibodies; the infant had severe but transient chylomicronemia. Two of the patients with chylomicronemia and GPIHBP1 autoantibodies had a response to treatment with immunosuppressive agents. CONCLUSIONS: In six patients with chylomicronemia, GPIHBP1 autoantibodies blocked the ability of GPIHBP1 to bind and transport lipoprotein lipase, thereby interfering with lipoprotein lipase-mediated processing of triglyceride-rich lipoproteins and causing severe hypertriglyceridemia. (Funded by the National Heart, Lung, and Blood Institute and the Leducq Foundation.).
[Mh] Termos MeSH primário: Autoanticorpos/sangue
Hiperlipoproteinemia Tipo I/imunologia
Lipase Lipoproteica/metabolismo
Receptores de Lipoproteínas/imunologia
[Mh] Termos MeSH secundário: Adulto
Autoanticorpos/fisiologia
Feminino
Seres Humanos
Hiperlipoproteinemia Tipo I/sangue
Imunoensaio
Lipólise
Lipase Lipoproteica/sangue
Masculino
Meia-Idade
Ligação Proteica
Transporte Proteico
Receptores de Lipoproteínas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Autoantibodies); 0 (GPIHBP1 protein, human); 0 (Receptors, Lipoprotein); EC 3.1.1.34 (Lipoprotein Lipase)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170413
[St] Status:MEDLINE
[do] DOI:10.1056/NEJMoa1611930


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[PMID]:28391899
[Au] Autor:Rosenson RS; Najera SD; Hegele RA
[Ad] Endereço:Cardiometabolics Unit, Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: robert.rosenson@mssm.edu.
[Ti] Título:Heterozygous familial hypercholesterolemia presenting as chylomicronemia syndrome.
[So] Source:J Clin Lipidol;11(1):294-296, 2017 Jan - Feb.
[Is] ISSN:1933-2874
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Heterozygous familial hypercholesterolemia (HeFH) is characterized by a twofold elevation in low-density lipoprotein cholesterol. Severe elevations in triglycerides are an uncommon manifestation. In this case report, we discuss an atypical presentation of the chylomicronemia syndrome in a patient with HeFH. Genetic analyses of the low-density lipoprotein receptor mutation and single nucleotide polymorphisms that elevate triglycerides provide confirmation for this atypical presentation of HeFH.
[Mh] Termos MeSH primário: Heterozigoto
Hiperlipoproteinemia Tipo II/complicações
Hiperlipoproteinemia Tipo II/genética
Hiperlipoproteinemia Tipo I/complicações
[Mh] Termos MeSH secundário: Adulto
Seres Humanos
Hiperlipoproteinemia Tipo II/sangue
Hiperlipoproteinemia Tipo II/diagnóstico
Masculino
Meia-Idade
Polimorfismo de Nucleotídeo Único
Triglicerídeos/sangue
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Triglycerides)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171023
[Lr] Data última revisão:
171023
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170411
[St] Status:MEDLINE


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[PMID]:28338353
[Au] Autor:Davidson M; Stevenson M; Hsieh A; Ahmad Z; Crowson C; Witztum JL
[Ad] Endereço:a Department of Medicine , University of Chicago , Chicago , IL , USA.
[Ti] Título:The burden of familial chylomicronemia syndrome: interim results from the IN-FOCUS study.
[So] Source:Expert Rev Cardiovasc Ther;15(5):415-423, 2017 May.
[Is] ISSN:1744-8344
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Familial Chylomicronemia Syndrome (FCS) is a rare genetic disorder that is caused by a decrease or an absence of lipoprotein lipase activity. FCS is characterized by marked accumulation of chylomicrons and extreme hypertriglyceridemia, which have major effects on both physical and mental health. To date, there have been no systematic efforts to characterize the impact of chylomicronemia on FCS patients' lives. In particular, the impact of FCS on the burden of illness (BoI) and quality of life (QoL) has not been fully described in the literature. METHODS: IN-FOCUS was a comprehensive web-based research survey of patients with FCS focused on capturing the BoI and impact on QoL associated with FCS. Sixty patients from the US diagnosed with FCS participated. Patients described multiple symptoms spanning across physical, emotional and cognitive domains. RESULTS: Patients on average cycled through 5 physicians of varying specialty before being diagnosed with FCS, reflecting a lengthy journey to diagnosis Nearly all respondents indicated that FCS had a major impact on BoI and QoL and significantly influenced their career choice and employment status, and caused significant work loss due to their disease. CONCLUSION: FCS imparts a considerable burden across multiple domains with reported impairment on activities of daily living and QoL.
[Mh] Termos MeSH primário: Efeitos Psicossociais da Doença
Hiperlipoproteinemia Tipo I/fisiopatologia
Qualidade de Vida
[Mh] Termos MeSH secundário: Atividades Cotidianas
Adulto
Quilomícrons/metabolismo
Feminino
Seres Humanos
Hipertrigliceridemia/etiologia
Masculino
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chylomicrons)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170724
[Lr] Data última revisão:
170724
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170325
[St] Status:MEDLINE
[do] DOI:10.1080/14779072.2017.1311786


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[PMID]:28201738
[Au] Autor:Ueda M; Dunbar RL; Wolska A; Sikora TU; Escobar MDR; Seliktar N; deGoma E; DerOhannessian S; Morrell L; McIntyre AD; Burke F; Sviridov D; Amar M; Shamburek RD; Freeman L; Hegele RA; Remaley AT; Rader DJ
[Ad] Endereço:Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104.
[Ti] Título:A Novel APOC2 Missense Mutation Causing Apolipoprotein C-II Deficiency With Severe Triglyceridemia and Pancreatitis.
[So] Source:J Clin Endocrinol Metab;102(5):1454-1457, 2017 May 01.
[Is] ISSN:1945-7197
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Context: Familial chylomicronemia syndrome (FCS) is a rare heritable disorder associated with severe hypertriglyceridemia and recurrent pancreatitis. Lipoprotein lipase deficiency and apolipoprotein C-II deficiency are two well-characterized autosomal recessive causes of FCS, and three other genes have been described to cause FCS. Because therapeutic approaches can vary according to the underlying etiology, it is important to establish the molecular etiology of FCS. Case Description: A man originally from North Africa was referred to the University of Pennsylvania Lipid Clinic for severe hypertriglyceridemia and recurrent pancreatitis, consistent with the clinical diagnosis of FCS. Molecular analyses of FCS-associated genes revealed a homozygous missense variant R72T in APOC2. Molecular modeling of the variant predicted that the apolipoprotein C-II R72T peptide has reduced lipid binding affinity. In vitro studies of the patient's plasma confirmed the lack of functional apoC-II activity. Moreover, the apoC-II protein was undetectable in the patient's plasma, quantitatively as well as qualitatively. Conclusions: We identified a missense APOC2 variant causing apoC-II deficiency in a patient with severe hypertriglyceridemia and recurrent pancreatitis. Beyond dietary management and usual pharmacologic therapies, an apoC-II mimetic peptide may become an optional therapy in patients with apoC-II deficiency in the future.
[Mh] Termos MeSH primário: Apolipoproteína C-II/genética
Hiperlipoproteinemia Tipo I/genética
Hipertrigliceridemia/metabolismo
Mutação de Sentido Incorreto
Pancreatite/metabolismo
[Mh] Termos MeSH secundário: Adulto
Grupo com Ancestrais do Continente Africano
Apolipoproteína C-II/deficiência
Homozigoto
Seres Humanos
Hiperlipoproteinemia Tipo I/complicações
Hiperlipoproteinemia Tipo I/metabolismo
Hipertrigliceridemia/etiologia
Masculino
Pancreatite/etiologia
Recidiva
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apolipoprotein C-II)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170911
[Lr] Data última revisão:
170911
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170216
[St] Status:MEDLINE
[do] DOI:10.1210/jc.2016-3903


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[PMID]:28107429
[Au] Autor:Liu C; Gaudet D; Miller YI
[Ad] Endereço:Department of Medicine, University of California San Diego, La Jolla, California, United States of America.
[Ti] Título:Deficient Cholesterol Esterification in Plasma of apoc2 Knockout Zebrafish and Familial Chylomicronemia Patients.
[So] Source:PLoS One;12(1):e0169939, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Hypertriglyceridemia is an independent risk factor for cardiovascular disease. Apolipoprotein C-II (APOC2) is an obligatory cofactor for lipoprotein lipase (LPL), the major enzyme catalyzing plasma triglyceride hydrolysis. We have created an apoc2 knockout zebrafish model, which mimics the familial chylomicronemia syndrome (FCS) in human patients with a defect in the APOC2 or LPL gene. In this study, we measured plasma levels of free cholesterol (FC) and cholesterol esters (CE) and found that apoc2 mutant zebrafish have a significantly higher FC to CE ratio (FC/CE), when compared to the wild type. Feeding apoc2 mutant zebrafish a low-fat diet reduced triglyceride levels but not the FC/CE ratio. In situ hybridization and qPCR results demonstrated that the hepatic expression of lecithin-cholesterol acyltransferase (lcat), the enzyme responsible for esterifying plasma FC to CE, and of apolipoprotein A-I, a major protein component of HDL, were dramatically decreased in apoc2 mutants. Furthermore, the FC/CE ratio was significantly increased in the whole plasma and in a chylomicron-depleted fraction of human FCS patients. The FCS plasma LCAT activity was significantly lower than that of healthy controls. In summary, this study, using a zebrafish model and human patient samples, reports for the first time the defect in plasma cholesterol esterification associated with LPL deficiency.
[Mh] Termos MeSH primário: Apolipoproteína C-II/genética
Colesterol/metabolismo
Hiperlipoproteinemia Tipo I/sangue
Peixe-Zebra/genética
[Mh] Termos MeSH secundário: Animais
Animais Geneticamente Modificados
Esterificação
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apolipoprotein C-II); 97C5T2UQ7J (Cholesterol)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170810
[Lr] Data última revisão:
170810
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170121
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0169939


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[PMID]:27998715
[Au] Autor:Stroes E; Moulin P; Parhofer KG; Rebours V; Löhr JM; Averna M
[Ad] Endereço:Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
[Ti] Título:Diagnostic algorithm for familial chylomicronemia syndrome.
[So] Source:Atheroscler Suppl;23:1-7, 2017 Jan.
[Is] ISSN:1878-5050
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Familial chylomicronemia syndrome (FCS) is a rare genetic disease that leads to severe hypertriglyceridemia often associated with recurrent episodes of pancreatitis. The recognition and correct diagnosis of the disease is challenging due to its rarity, and to the lack of specificity of signs and symptoms. Lipid experts, endocrinologists, gastroenterologists, pancreatologists, and general practitioners may encounter patients who potentially have FCS. Therefore, cooperation between experts and improved knowledge of FCS is essential in improving the diagnosis. Currently, a consensus on best practice for the diagnosis of FCS is lacking. METHODS: Aiming to define a diagnostic algorithm for FCS, a board of European experts was instituted. Such an algorithm for FCS is important to guide practitioners in the diagnosis of suspected FCS and to optimize therapeutic strategies. RESULTS: The multidisciplinary views were merged, leading to a diagnostic algorithm, proposed here. CONCLUSION: This diagnostic algorithm represents a potentially useful tool to support primary and secondary care practitioners in the recognition of signs and clinical manifestations in individuals potentially affected by FCS.
[Mh] Termos MeSH primário: Algoritmos
Procedimentos Clínicos
Análise Mutacional de DNA
Técnicas de Apoio para a Decisão
Hiperlipoproteinemia Tipo I/diagnóstico
Lipídeos/sangue
Lipase Lipoproteica/genética
Mutação
[Mh] Termos MeSH secundário: Biomarcadores/sangue
Marcadores Genéticos
Predisposição Genética para Doença
Seres Humanos
Hiperlipoproteinemia Tipo I/sangue
Hiperlipoproteinemia Tipo I/genética
Hiperlipoproteinemia Tipo I/terapia
Fenótipo
Guias de Prática Clínica como Assunto
Valor Preditivo dos Testes
Prognóstico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Genetic Markers); 0 (Lipids); EC 3.1.1.34 (LPL protein, human); EC 3.1.1.34 (Lipoprotein Lipase)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170213
[Lr] Data última revisão:
170213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161222
[St] Status:MEDLINE


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[PMID]:27828598
[Au] Autor:Tang M; Zong P; Zhang T; Wang D; Wang Y; Zhao Y
[Ad] Endereço:MD, Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China. Conception and design of the study, analysis of data, manuscript writing, final approved.
[Ti] Título:Lipoprotein lipase gene-deficient mice with hypertriglyceridaemia associated with acute pancreatitis.
[So] Source:Acta Cir Bras;31(10):655-660, 2016 Oct.
[Is] ISSN:1678-2674
[Cp] País de publicação:Brazil
[La] Idioma:eng
[Ab] Resumo:PURPOSE: : To investigate the severity of pancreatitis in lipoprotein lipase (LPL)-deficient hypertriglyceridaemic (HTG) heterozygous mice and to establish an experimental animal model for HTG pancreatitis study. METHODS:: LPL-deficient HTG heterozygous mice were rescued by somatic gene transfer and mated with wild-type mice. The plasma amylase, triglyceride, and pathologic changes in the pancreas of the LPL-deficient HTG heterozygous mice were compared with those of wild-type mice to assess the severity of pancreatitis. In addition, acute pancreatitis (AP) was induced by caerulein (50 µg/kg) for further assessment. RESULTS:: The levels of plasma amylase and triglyceride were significantly higher in the LPL-deficient HTG heterozygous mice. According to the pancreatic histopathologic scores, the LPL-deficient HTG heterozygous mice showed more severe pathologic damage than the wild-type mice. CONCLUSIONS: : Lipoprotein lipase deficient heterozygous mice developed severe caerulein-induced pancreatitis. In addition, their high triglyceride levels were stable. Therefore, LPL-deficient HTG heterozygous mice are a useful experimental model for studying HTG pancreatitis.
[Mh] Termos MeSH primário: Hiperlipoproteinemia Tipo I/complicações
Hipertrigliceridemia/complicações
Pancreatite/etiologia
[Mh] Termos MeSH secundário: Doença Aguda
Amilases/sangue
Animais
Modelos Animais de Doenças
Feminino
Heterozigoto
Hiperlipoproteinemia Tipo I/genética
Camundongos Endogâmicos C57BL
Pancreatite/patologia
Índice de Gravidade de Doença
Fatores de Tempo
Triglicerídeos/sangue
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Triglycerides); EC 3.2.1.- (Amylases)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170526
[Lr] Data última revisão:
170526
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161110
[St] Status:MEDLINE


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[PMID]:27578137
[Au] Autor:Patni N; Brothers J; Xing C; Garg A
[Ad] Endereço:Division of Pediatric Endocrinology, Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, USA.
[Ti] Título:Type 1 hyperlipoproteinemia in a child with large homozygous deletion encompassing GPIHBP1.
[So] Source:J Clin Lipidol;10(4):1035-1039.e2, 2016 Jul-Aug.
[Is] ISSN:1933-2874
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Type I hyperlipoproteinemia (T1HLP) usually presents with extreme hypertriglyceridemia, recurrent episodes of acute pancreatitis, lipemia retinalis, and cutaneous eruptive xanthomas. We report a unique 10-year-old male of Indian origin who presented in neonatal period with transient obstructive jaundice and xanthomas in the pancreas and kidneys. Serum triglycerides stabilized with extremely low-fat diet although he subsequently developed pancreatic atrophy. Extreme hypertriglyceridemia failed to respond to treatment with fenofibrate, fish oil, and orlistat. Whole-exome sequencing of the parents and patient was performed. Copy number variation analysis revealed a large deletion in chromosome 8 containing the entire GPIHBP1, which was confirmed by Sanger sequencing to be 54,623 bp deletion. Review of the literature revealed a slightly higher maximum triglyceride levels in those with homozygous null vs missense mutations suggesting severe disease in those with nonfunctional vs dysfunctional GPIHBP1 protein. Visceral xanthomas and pancreatic atrophy can be part of the spectrum of clinical features in patients with T1HLP. We highlight the need to perform copy number variations analysis of whole-exome sequencing data for finding disease-causing variants. There is also an urgent need to develop novel targeted therapies for patients with T1HLP.
[Mh] Termos MeSH primário: Deleção de Genes
Homozigoto
Hiperlipoproteinemia Tipo I/genética
Receptores de Lipoproteínas/deficiência
Receptores de Lipoproteínas/genética
[Mh] Termos MeSH secundário: Adolescente
Sequência de Bases
Genótipo
Seres Humanos
Masculino
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (GPIHBP1 protein, human); 0 (Receptors, Lipoprotein)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160901
[St] Status:MEDLINE


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[PMID]:27578123
[Au] Autor:Rabacchi C; D'Addato S; Palmisano S; Lucchi T; Bertolini S; Calandra S; Tarugi P
[Ad] Endereço:Department of Life Sciences, University of Modena and Reggio Emilia, Italy.
[Ti] Título:Clinical and genetic features of 3 patients with familial chylomicronemia due to mutations in GPIHBP1 gene.
[So] Source:J Clin Lipidol;10(4):915-921.e4, 2016 Jul-Aug.
[Is] ISSN:1933-2874
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Familial chylomicronemia is a recessive disorder that may be due to mutations in lipoprotein lipase (LPL) and in other proteins such as apolipoprotein C-II and apolipoprotein A-V (activators of LPL), GPIHBP1 (the molecular platform required for LPL activity on endothelial surface), and LMF1 (a factor required for intracellular formation of active LPL). METHODS: We sequenced the familial chylomicronemia candidate genes in 2 adult females presenting long-standing hypertriglyceridemia and a history of acute pancreatitis. RESULTS: Both probands had plasma triglyceride >10 mmol/L but no mutations in the LPL gene. The sequence of the other candidate genes showed that one patient was homozygous for a novel missense mutation p.(Cys83Arg), and the other was homozygous for a previously reported nonsense mutation p.(Cys 89*), respectively, in GPIHBP1. Family screening showed that the hypertriglyceridemic brother of the p.(Cys83Arg) homozygote was also homozygous for this mutation. He had no history of pancreatitis. The p.(Cys83Arg) heterozygous carriers had normal triglyceride levels. The substitution of a cysteine residue in the Ly6 domain of GPIHBP1 is predicted to abolish one of the disulfide bridges required to maintain the structure of GPIHBP1. The p.(Cys89*) mutation results in a truncated protein devoid of function. CONCLUSIONS: Both mutant GPIHBP1 proteins are expected to be incapable of transferring LPL from the subendothelial space to the endothelial surface.
[Mh] Termos MeSH primário: Códon sem Sentido
Hiperlipoproteinemia Tipo I/genética
Mutação de Sentido Incorreto
Receptores de Lipoproteínas/genética
[Mh] Termos MeSH secundário: Adulto
Sequência de Bases
Feminino
Homozigoto
Seres Humanos
Hiperlipoproteinemia Tipo I/diagnóstico
Achados Incidentais
Masculino
Meia-Idade
Linhagem
Domínios Proteicos
Receptores de Lipoproteínas/química
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Codon, Nonsense); 0 (GPIHBP1 protein, human); 0 (Receptors, Lipoprotein)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160901
[St] Status:MEDLINE


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[PMID]:27578112
[Au] Autor:Pingitore P; Lepore SM; Pirazzi C; Mancina RM; Motta BM; Valenti L; Berge KE; Retterstøl K; Leren TP; Wiklund O; Romeo S
[Ad] Endereço:Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
[Ti] Título:Identification and characterization of two novel mutations in the LPL gene causing type I hyperlipoproteinemia.
[So] Source:J Clin Lipidol;10(4):816-823, 2016 Jul-Aug.
[Is] ISSN:1933-2874
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Type 1 hyperlipoproteinemia is a rare autosomal recessive disorder most often caused by mutations in the lipoprotein lipase (LPL) gene resulting in severe hypertriglyceridemia and pancreatitis. OBJECTIVES: The aim of this study was to identify novel mutations in the LPL gene causing type 1 hyperlipoproteinemia and to understand the molecular mechanisms underlying the severe hypertriglyceridemia. METHODS: Three patients presenting classical features of type 1 hyperlipoproteinemia were recruited for DNA sequencing of the LPL gene. Pre-heparin and post-heparin plasma of patients were used for protein detection analysis and functional test. Furthermore, in vitro experiments were performed in HEK293 cells. Protein synthesis and secretion were analyzed in lysate and medium fraction, respectively, whereas medium fraction was used for functional assay. RESULTS: We identified two novel mutations in the LPL gene causing type 1 hyperlipoproteinemia: a two base pair deletion (c.765_766delAG) resulting in a frameshift at position 256 of the protein (p.G256TfsX26) and a nucleotide substitution (c.1211 T > G) resulting in a methionine to arginine substitution (p.M404 R). LPL protein and activity were not detected in pre-heparin or post-heparin plasma of the patient with p.G256TfsX26 mutation or in the medium of HEK293 cells over-expressing recombinant p.G256TfsX26 LPL. A relatively small amount of LPL p.M404 R was detected in both pre-heparin and post-heparin plasma and in the medium of the cells, whereas no LPL activity was detected. CONCLUSIONS: We conclude that these two novel mutations cause type 1 hyperlipoproteinemia by inducing a loss or reduction in LPL secretion accompanied by a loss of LPL enzymatic activity.
[Mh] Termos MeSH primário: Hiperlipoproteinemia Tipo I/enzimologia
Hiperlipoproteinemia Tipo I/genética
Lipase Lipoproteica/genética
[Mh] Termos MeSH secundário: Adulto
Análise Mutacional de DNA
Feminino
Células HEK293
Seres Humanos
Hiperlipoproteinemia Tipo I/sangue
Hiperlipoproteinemia Tipo I/metabolismo
Lipase Lipoproteica/biossíntese
Lipase Lipoproteica/sangue
Lipase Lipoproteica/secreção
Masculino
Mutação
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.1.1.34 (Lipoprotein Lipase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160901
[St] Status:MEDLINE



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