Structural and functional analysis of APOA5 mutations identified in patients with severe hypertriglyceridemia

During the diagnosis of three unrelated patients with severe hypertriglyceridemia, three APOA5 mutations [p.(Ser232_Leu235)del,p.Leu253Pro,andp.Asp332ValfsX4] were found without evidence of concomitant LPL, APOC2, or GPIHBP1 mutations. The molecular mechanisms by which APOA5 mutations result in seve...

Descripción completa

Detalles Bibliográficos
Autores: Mendoza-Barbera, E, Julve, J, Nilsson, SK, Lookene, A, Martin-Campos, JM, Roig, R, Lechuga-Sancho, AM, Sloan, JH, Fuentes-Prior, P, Blanco-Vaca, F
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2013
País:España
Institución:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositorio:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p10883
Acceso en línea:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=10883
Access Level:acceso abierto
Palabra clave:apoA-V
familial hyperchylomicronemia
homology modeling
molecular bases of disease
LRP1
sortilin
SorLA/LR11
triglyceride metabolism
type V hyperlipidemia
id ES_259265dfd54bc15a494378366fc47842
oai_identifier_str oai:iibsantpau.fundanetsuite.com:p10883
network_acronym_str ES
network_name_str España
repository_id_str
spelling Structural and functional analysis of APOA5 mutations identified in patients with severe hypertriglyceridemiaMendoza-Barbera, EJulve, JNilsson, SKLookene, AMartin-Campos, JMRoig, RLechuga-Sancho, AMSloan, JHFuentes-Prior, PBlanco-Vaca, FapoA-Vfamilial hyperchylomicronemiahomology modelingmolecular bases of diseaseLRP1sortilinSorLA/LR11triglyceride metabolismtype V hyperlipidemiaDuring the diagnosis of three unrelated patients with severe hypertriglyceridemia, three APOA5 mutations [p.(Ser232_Leu235)del,p.Leu253Pro,andp.Asp332ValfsX4] were found without evidence of concomitant LPL, APOC2, or GPIHBP1 mutations. The molecular mechanisms by which APOA5 mutations result in severe hypertriglyceridemia remain poorly understood, and the functional impairment/s induced by these specific mutations was not obvious. Therefore, we performed a thorough structural and functional analysis that included follow-up of patients and their closest relatives, measurement of apoA-V serum concentrations, and sequencing of the APOA5 gene in 200 nonhyperlipidemic controls. Further, we cloned, overexpressed, and purified both wild-type and mutant apoA-V variants and characterized their capacity to activate LPL. The interactions of recombinant wild-type and mutated apoA-V variants with liposomes of different composition, heparin, LRP1, sortilin, and SorLA/LR11 were also analyzed. Finally, to explore the possible structural consequences of these mutations, we developed a three-dimensional model of full-length, lipid-free human apoA-V. A complex, wide array of impairments was found in each of the three mutants, suggesting that the specific residues affected are critical structural determinants for apoA-V function in lipoprotein metabolism and, therefore, that these APOA5 mutations are a direct cause of hypertriglyceridemia.-Mendoza-Barbera, E., J. Julve, S. K. Nilsson, A. Lookene, J. M. Martin-Campos, R. Roig, A. M. Lechuga-Sancho, J. J. Sloan, P. Fuentes-Prior, and F. Blanco-Vaca. Structural and functional analysis of APOA5 mutations identified in patients with severe hypertriglyceridemia. J. Lipid Res. 2013. 54: 649-661.AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC2013info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=10883JOURNAL OF LIPID RESEARCHISSN: 00222275ISSNe: 15397262reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pauinstname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)Inglésinfo:eu-repo/semantics/openAccessoai:iibsantpau.fundanetsuite.com:p108832026-06-14T12:41:47Z
dc.title.none.fl_str_mv Structural and functional analysis of APOA5 mutations identified in patients with severe hypertriglyceridemia
title Structural and functional analysis of APOA5 mutations identified in patients with severe hypertriglyceridemia
spellingShingle Structural and functional analysis of APOA5 mutations identified in patients with severe hypertriglyceridemia
Mendoza-Barbera, E
apoA-V
familial hyperchylomicronemia
homology modeling
molecular bases of disease
LRP1
sortilin
SorLA/LR11
triglyceride metabolism
type V hyperlipidemia
title_short Structural and functional analysis of APOA5 mutations identified in patients with severe hypertriglyceridemia
title_full Structural and functional analysis of APOA5 mutations identified in patients with severe hypertriglyceridemia
title_fullStr Structural and functional analysis of APOA5 mutations identified in patients with severe hypertriglyceridemia
title_full_unstemmed Structural and functional analysis of APOA5 mutations identified in patients with severe hypertriglyceridemia
title_sort Structural and functional analysis of APOA5 mutations identified in patients with severe hypertriglyceridemia
dc.creator.none.fl_str_mv Mendoza-Barbera, E
Julve, J
Nilsson, SK
Lookene, A
Martin-Campos, JM
Roig, R
Lechuga-Sancho, AM
Sloan, JH
Fuentes-Prior, P
Blanco-Vaca, F
author Mendoza-Barbera, E
author_facet Mendoza-Barbera, E
Julve, J
Nilsson, SK
Lookene, A
Martin-Campos, JM
Roig, R
Lechuga-Sancho, AM
Sloan, JH
Fuentes-Prior, P
Blanco-Vaca, F
author_role author
author2 Julve, J
Nilsson, SK
Lookene, A
Martin-Campos, JM
Roig, R
Lechuga-Sancho, AM
Sloan, JH
Fuentes-Prior, P
Blanco-Vaca, F
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv apoA-V
familial hyperchylomicronemia
homology modeling
molecular bases of disease
LRP1
sortilin
SorLA/LR11
triglyceride metabolism
type V hyperlipidemia
topic apoA-V
familial hyperchylomicronemia
homology modeling
molecular bases of disease
LRP1
sortilin
SorLA/LR11
triglyceride metabolism
type V hyperlipidemia
description During the diagnosis of three unrelated patients with severe hypertriglyceridemia, three APOA5 mutations [p.(Ser232_Leu235)del,p.Leu253Pro,andp.Asp332ValfsX4] were found without evidence of concomitant LPL, APOC2, or GPIHBP1 mutations. The molecular mechanisms by which APOA5 mutations result in severe hypertriglyceridemia remain poorly understood, and the functional impairment/s induced by these specific mutations was not obvious. Therefore, we performed a thorough structural and functional analysis that included follow-up of patients and their closest relatives, measurement of apoA-V serum concentrations, and sequencing of the APOA5 gene in 200 nonhyperlipidemic controls. Further, we cloned, overexpressed, and purified both wild-type and mutant apoA-V variants and characterized their capacity to activate LPL. The interactions of recombinant wild-type and mutated apoA-V variants with liposomes of different composition, heparin, LRP1, sortilin, and SorLA/LR11 were also analyzed. Finally, to explore the possible structural consequences of these mutations, we developed a three-dimensional model of full-length, lipid-free human apoA-V. A complex, wide array of impairments was found in each of the three mutants, suggesting that the specific residues affected are critical structural determinants for apoA-V function in lipoprotein metabolism and, therefore, that these APOA5 mutations are a direct cause of hypertriglyceridemia.-Mendoza-Barbera, E., J. Julve, S. K. Nilsson, A. Lookene, J. M. Martin-Campos, R. Roig, A. M. Lechuga-Sancho, J. J. Sloan, P. Fuentes-Prior, and F. Blanco-Vaca. Structural and functional analysis of APOA5 mutations identified in patients with severe hypertriglyceridemia. J. Lipid Res. 2013. 54: 649-661.
publishDate 2013
dc.date.none.fl_str_mv 2013
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=10883
url https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=10883
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
publisher.none.fl_str_mv AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
dc.source.none.fl_str_mv JOURNAL OF LIPID RESEARCH
ISSN: 00222275
ISSNe: 15397262
reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
instname_str Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
reponame_str r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
collection r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869404770447392768
score 15,812429

Similares en LA Referencia