title: Identification and characterization of LDL receptor gene mutations in hyperlipidemic Chinese.
abstract: 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.
authors.affiliation: Department of Biology, National Taiwan Normal University, Taipei, Taiwan.
authors.forename: Jui-Hung
authors.initials: JH
authors.lastname: Chang
authors.forename: Ju-Pin
authors.initials: JP
authors.lastname: Pan
authors.forename: Der-Yan
authors.initials: DY
authors.lastname: Tai
authors.forename: Ai-Chun
authors.initials: AC
authors.lastname: Huang
authors.forename: Pi-Hung
authors.initials: PH
authors.lastname: Li
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Ho
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Hsieh
authors.forename: Shiu-Ching
authors.initials: SC
authors.lastname: Chou
authors.forename: Wen-Lang
authors.initials: WL
authors.lastname: Lin
authors.forename: Eric
authors.initials: E
authors.lastname: Lo
authors.forename: Ching-Yu
authors.initials: CY
authors.lastname: Chang
authors.forename: Jerming
authors.initials: J
authors.lastname: Tseng
authors.forename: Ming-Tsan
authors.initials: MT
authors.lastname: Su
authors.forename: Guey-Jen
authors.initials: GJ
authors.lastname: Lee-Chen
mesh_terms: 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
chemical_list: D018076:DNA, Complementary; D011973:Receptors, LDL