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Journal of Lipid Research, Vol. 44, 1850-1858, October 2003
Copyright © 2003 by American Society for Biochemistry and Molecular Biology

Identification and characterization of LDL receptor gene mutations in hyperlipidemic Chinese

Jui-Hung Chang^*, Ju-Pin Pan^,, Der-Yan Tai^**, Ai-Chun Huang^*, Pi-Hung Li^*, Hui-Ling Ho^*, Hui-Ling Hsieh^*, Shiu-Ching Chou, Wen-Lang Lin^*, Eric Lo^*, Ching-Yu Chang^*, Jerming Tseng^*, Ming-Tsan Su^* and Guey-Jen Lee-Chen^1,*

^* Department of Biology, National Taiwan Normal University, Taipei, Taiwan
Division of Cardiology, Department of Medicine, Veterans General Hospital-Taipei, Taipei, Taiwan
School of Medicine, National Yang-Ming University, Taipei, Taiwan
^** Department of Internal Medicine, Wei Gong Memorial Hospital, Tou Fen, Miaoli, Taiwan

¹ To whom correspondence should be addressed. e-mail: t43019{at}cc.ntnu.edu.tw

DNA screening for LDL receptor mutations was performed in 170 unrelated hyperlipidemic Chinese patients and two clinically diagnosed familial hypercholesterolemia patients. Two deletions (Del e3-5 and Del e6-8), eight point mutations (W-18X, D69N, R94H, E207K, C308Y, I402T, A410T, and A696G), and two polymorphisms (A370T and I602V) were identified. Of these mutations, C308Y and Del e6-8 were found in homozygosity, and D69N and C308Y were seen in unrelated patients. The effects of mutations on LDL receptor function were characterized in COS-7 cells. The LDL receptor level and activity were close to those of wild type in A696G transfected cells. A novel intermediate protein and reduction of LDL receptor activity were seen in D69N transfected cells. For R94H, E207K, C308Y, I402T, and A410T mutations, only 20–64% of normal receptor activities were seen. Conversely, Del e3-5 and Del e6-8 lead to defective proteins with 0–13% activity. Most of the mutant receptors were localized intracellularly, with a staining pattern resembling that of the endoplasmic reticulum and Golgi apparatus (D69N, R94H, E207K, C308Y, and I402T) or endosome/lysosome (A410T and Del e6-8).

Molecular analysis of the LDL receptor gene will clearly identify the cause of the patient's hyperlipidemia and allow appropriate early treatment as well as antenatal and family studies.

Abbreviations: CAD, coronary artery disease; FH, familial hypercholesterolemia; SSCP, single-strand conformation polymorphism

Supplementary key words low density lipoprotein receptor mutation • cDNA expression • haplotype analysis

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