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 0.06 mmol/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.
Conclusion
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.
Keywords
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Article info
Publication history
Published online: September 18, 2009
Accepted:
August 19,
2009
Received in revised form:
August 18,
2009
Received:
July 10,
2009
Identification
Copyright
© 2009 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.
