Identification and characterization of LDL receptor gene mutations in hyperlipidemic Chinese.
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 approximately 20-64% of normal receptor activities were seen. Conversely, Del e3-5 and Del e6-8 lead to defective proteins with approximately 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.
Chang
Jui-Hung
JH
Department of Biology, National Taiwan Normal University, Taipei, Taiwan.
Pan
Ju-Pin
JP
Tai
Der-Yan
DY
Huang
Ai-Chun
AC
Li
Pi-Hung
PH
Ho
Hui-Ling
HL
Hsieh
Hui-Ling
HL
Chou
Shiu-Ching
SC
Lin
Wen-Lang
WL
Lo
Eric
E
Chang
Ching-Yu
CY
Tseng
Jerming
J
Su
Ming-Tsan
MT
Lee-Chen
Guey-Jen
GJ
D000818:Animals; D044466:Asian People; D001483:Base Sequence; D019556:COS Cells; D018076:DNA, Complementary / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D005091:Exons; D006056:Golgi Apparatus / Q000378:metabolism; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics*; D008247:Lysosomes / Q000378:metabolism; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation; D011110:Polymorphism, Genetic; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
D018076:DNA, Complementary; D011973:Receptors, LDL