A case of Tangier disease with a novel mutation in the C-terminal region of ATP-binding cassette transporter A1.
Tangier disease (TD), a rare disorder characterized by extremely low levels of high density lipoprotein cholesterol (HDL-C), is caused by mutations in the ATP-binding cassette transporter A1 (ABCA1) gene. Here, we describe a new patient with TD. The 42-year-old proband had obvious juvenile cataracts, mild hepatosplenomegaly, and an extremely low level of HDL-C (1 mg/dl), consistent with the diagnosis of TD. The proband was homozygous for a novel CTC6914-6TT --> 2203X mutation in the carboxy terminus of the ABCA1 protein. ApoAI-mediated cholesterol efflux from patient fibroblasts was markedly decreased compared to control, despite normal levels of protein expression. This indicates that this mutant protein is normally transcribed and exists as a stable product, yet is functionally defective. These results point to a critical role for the intracellular C-terminal region of the ABCA1 gene product in regulating cholesterol efflux and HDL-cholesterol levels.
Guan
Jing-Zhi
JZ
Third Department of Internal Medicine, Hirosaki University School of Medicine, 5-Zaifu, Hirosaki 036-8562, Japan.
Tamasawa
Naoki
N
Brunham
Liam R
LR
Matsui
Jun
J
Murakami
Hiroshi
H
Suda
Toshihiro
T
Ochiai
Shigeru
S
Tsutsui
Masahiro
M
Kudou
Kenji
K
Satoh
Kei
K
Hayden
Michael R
MR
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D015153:Blotting, Western; D002386:Cataract / Q000235:genetics; D008076:Cholesterol, HDL / Q000097:blood; D004252:DNA Mutational Analysis; D005260:Female; D006529:Hepatomegaly / Q000235:genetics; D006801:Humans; D013163:Splenomegaly / Q000235:genetics; D013631:Tangier Disease / Q000235:genetics*
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D008076:Cholesterol, HDL