title: Tangier disease caused by compound heterozygosity for ABCA1 mutations R282X and Y1532C.
abstract: BACKGROUND
  Inherited low levels of high density lipoprotein (HDL) cholesterol may be due to mutations in the genes encoding the ATP-binding cassette transporter A1 (ABCA1), apolipoprotein (apo) A-I or lecithin:cholesterol acyltransferase (LCAT).
  
  
  METHODS
  The ABCA1, apoA-I and LCAT genes of a 40-year-old male subject with serum HDL cholesterol of 0.06mmol/l were subjected to DNA sequencing. The proband's family was examined for co-segregation between mutations and levels of HDL cholesterol. Cholesterol efflux in fibroblasts from the proband and a normocholesterolemic subject was compared. The effects of an ABCA1 mutation on cholesterol efflux and membrane localization of ABCA1 were studied in transfected HEK293 and HeLa cells, respectively.
  
  
  RESULTS
  The proband was a compound heterozygote for ABCA1 mutations R282X (c.844 C>T) and Y1532C (c.4595 A>G). Relatives who were heterozygous for one of these mutations, had about half-normal HDL cholesterol levels. Cholesterol efflux was reduced in fibroblasts from the proband, as was cholesterol efflux from HEK293 cells transfected with an human (h) ABCA1 expression plasmid harboring the Y1532C mutation. Confocal microscopy of HeLa cells transfected with the Y1532C-hABCA1 plasmid revealed that the Y1532C mutation inhibits ABCA1 from reaching the cellular membrane.
  
  
  CONCLUSIONS
  Compound heterozygosity for the nonsense mutation R282X and the missense mutation Y1532C in the ABCA1 gene causes Tangier disease. R282X has a detrimental effect on the function of ABCA1 since a premature stop codon is introduced. Mutation Y1532C disrupts the normal function of ABCA1 as determined by in vitro analyses.
authors.affiliation: Medical Genetics Laboratory, Department of Medical Genetics, Rikshospitalet, Oslo University Hospital, Oslo, Norway.
authors.forename: Jamie
authors.initials: J
authors.lastname: Cameron
authors.forename: Trine
authors.initials: T
authors.lastname: Ranheim
authors.forename: Bente
authors.initials: B
authors.lastname: Halvorsen
authors.forename: Mari Ann
authors.initials: MA
authors.lastname: Kulseth
authors.forename: Trond P
authors.initials: TP
authors.lastname: Leren
authors.forename: Knut Erik
authors.initials: KE
authors.lastname: Berge
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D019943:Amino Acid Substitution; D008076:Cholesterol, HDL / Q000097:blood; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D006579:Heterozygote; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D009664:Norway; D010375:Pedigree; D013631:Tangier Disease / Q000097:blood / Q000235:genetics*
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D008076:Cholesterol, HDL; D018389:Codon, Nonsense