title: Identification and characterization of novel loss of function mutations in ATP-binding cassette transporter A1 in patients with low plasma high-density lipoprotein cholesterol.
abstract: OBJECTIVE
  The current literature provides little information on the frequency of mutations in the ATP-binding cassette transporter A1 (ABCA1) in patients with low high-density lipoprotein cholesterol (HDL) levels that are referred to the clinic. In 78 patients with low plasma levels of HDL cholesterol that were referred to our clinic, we routinely screened for ABCA1 gene mutations and studied the functionality of newly identified ABCA1 missense mutations.
  
  
  METHODS
  The coding regions and exon-intron boundaries of the ABCA1 gene were sequenced in 78 subjects with HDL cholesterol levels below the 10th percentile for age and gender. Novel mutations were studied by assessing cholesterol efflux capacity (using apolipoprotein A-I as acceptor) after transient expression of ABCA1 variants in BHK cells.
  
  
  RESULTS
  Sixteen out of 78 patients (21%) were found to carry 19 different ABCA1 gene variants (1 frameshift, 2 splice-site, 4 nonsense and 12 missense variation) of which 14 variations were novel. Of three patients with homozygous mutations and three patients having compound heterozygous mutations only one patient presented with the clinical characteristics of Tangier Disease (TD) in the presence of nearly complete HDL deficiency. Seven out of eight newly identified ABCA1 missense mutations were found to exhibit a statistically significant loss of cholesterol efflux capacity.
  
  
  CONCLUSIONS
  This study shows that one out of five patients who are referred to our hospital because of low HDL cholesterol levels have a functional ABCA1 gene mutation. It is furthermore demonstrated that in vitro studies are needed to assess functionality of ABCA1 missense mutations.
authors.affiliation: Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Candini
authors.forename: A W
authors.initials: AW
authors.lastname: Schimmel
authors.forename: J
authors.initials: J
authors.lastname: Peter
authors.forename: A E
authors.initials: AE
authors.lastname: Bochem
authors.forename: A G
authors.initials: AG
authors.lastname: Holleboom
authors.forename: M
authors.initials: M
authors.lastname: Vergeer
authors.forename: R P F
authors.initials: RP
authors.lastname: Dullaart
authors.forename: G M
authors.initials: GM
authors.lastname: Dallinga-Thie
authors.forename: G K
authors.initials: GK
authors.lastname: Hovingh
authors.forename: K L
authors.initials: KL
authors.lastname: Khoo
authors.forename: T
authors.initials: T
authors.lastname: Fasano
authors.forename: L
authors.initials: L
authors.lastname: Bocchi
authors.forename: S
authors.initials: S
authors.lastname: Calandra
authors.forename: J A
authors.initials: JA
authors.lastname: Kuivenhoven
authors.forename: M M
authors.initials: MM
authors.lastname: Motazacker
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood*; D006224:Cricetinae; D006801:Humans; D020125:Mutation, Missense
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D008076:Cholesterol, HDL; D002784:Cholesterol