title: Two novel missense mutations in ABCA1 result in altered trafficking and cause severe autosomal recessive HDL deficiency.
abstract: 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.
authors.affiliation: MRC Clinical Sciences Centre, Hammersmith Hospital, Faculty of Medicine, Imperial College, Du Cane Road, London W12 ONN, UK.
authors.forename: Christiane
authors.initials: C
authors.lastname: Albrecht
authors.forename: Kevin
authors.initials: K
authors.lastname: Baynes
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sardini
authors.forename: Silke
authors.initials: S
authors.lastname: Schepelmann
authors.forename: Emily R
authors.initials: ER
authors.lastname: Eden
authors.forename: Simon W
authors.initials: SW
authors.lastname: Davies
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Higgins
authors.forename: Michael D
authors.initials: MD
authors.lastname: Feher
authors.forename: James S
authors.initials: JS
authors.lastname: Owen
authors.forename: Anne K
authors.initials: AK
authors.lastname: Soutar
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics; D002478:Cells, Cultured; D005091:Exons / Q000235:genetics; D005260:Female; D005347:Fibroblasts; D005786:Gene Expression Regulation; D005808:Genes, Recessive / Q000235:genetics*; D006801:Humans; D008075:Lipoproteins, HDL / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D012333:RNA, Messenger