Identification and characterization of two novel mutations in the LPL gene causing type I hyperlipoproteinemia.
J Clin Lipidol
; 10(4): 816-823, 2016.
Article
em En
| MEDLINE
| ID: mdl-27578112
ABSTRACT
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Lipase Lipoproteica
/
Hiperlipoproteinemia Tipo I
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Limite:
Adult
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
J Clin Lipidol
Assunto da revista:
BIOQUIMICA
/
METABOLISMO
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Suécia