Two novel missense mutations in ABCA1 result in altered trafficking and cause severe autosomal recessive HDL deficiency
| Autor: | Christopher F. Higgins, Christiane Albrecht, James S. Owen, Simon W Davies, Michael D. Feher, Emily R. Eden, Kevin C.R. Baynes, Anne K. Soutar, Silke Schepelmann, Alessandro Sardini |
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| Rok vydání: | 2003 |
| Předmět: |
Proband
Male Apolipoprotein B ABCA1 030204 cardiovascular system & hematology medicine.disease_cause chemistry.chemical_compound 0302 clinical medicine Tangier disease Missense mutation Cholesterol efflux Cells Cultured Genetics 0303 health sciences Mutation biology Exons Pedigree Protein Transport Molecular Medicine lipids (amino acids peptides and proteins) Female Lipoproteins HDL ATP Binding Cassette Transporter 1 Adult Adolescent Protein trafficking Molecular Sequence Data Mutation Missense Genes Recessive 03 medical and health sciences medicine Animals Humans Amino Acid Sequence RNA Messenger Molecular Biology 030304 developmental biology Aged Apolipoprotein AI Apolipoprotein A-I Cholesterol nutritional and metabolic diseases Fibroblasts medicine.disease Molecular biology HDL deficiency chemistry Gene Expression Regulation biology.protein ATP-Binding Cassette Transporters Sequence Alignment |
| Zdroj: | Biochimica et biophysica acta. 1689(1) |
| ISSN: | 0006-3002 |
| Popis: | Extremely low concentrations of high density lipoprotein (HDL)-cholesterol and apolipoprotein (apo) AI are features of Tangier disease caused by autosomal recessive mutations in ATP-binding cassette transporter A1 (ABCA1). Less deleterious, but dominantly inherited mutations cause HDL deficiency. We investigated causes of severe HDL deficiency in a 42-year-old female with progressive coronary disease.ApoAI-mediated efflux of cholesterol from the proband's fibroblasts was less than 10% of normal and nucleotide sequencing revealed inheritance of two novel mutations in ABCAI, V1704D and L1379F. ABCA1 mRNA was approximately 3-fold higher in the proband's cells than in control cells; preincubation with cholesterol increased it 5-fold in control and 8-fold in the proband's cells, but similar amounts of ABCA1 protein were present in control and mutant cells. When transiently transfected into HEK293 cells, confocal microscopy revealed that both mutant proteins were retained in the endoplasmic reticulum, while wild-type ABCA1 was located at the plasma membrane.Severe HDL deficiency in the proband was caused by two novel autosomal recessive mutations in ABCA1, one (V1704D) predicted to lie in a transmembrane segment and the other (L1379F) in a large extracellular loop. Both mutations prevent normal trafficking of ABCA1, thereby explaining their inability to mediate apoA1-dependent lipid efflux. |
| Databáze: | OpenAIRE |
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