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, Guey Jen Lee-Chen

Research output: Contribution to journalArticle

35 Citations (Scopus)

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, 1402T, 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.

Original languageEnglish
Pages (from-to)1850-1858
Number of pages9
JournalJournal of Lipid Research
Volume44
Issue number10
DOIs
Publication statusPublished - 2003 Oct 1

Fingerprint

LDL Receptors
Genes
Mutation
Hyperlipoproteinemia Type II
Endosomes
COS Cells
Golgi Apparatus
Lysosomes
Hyperlipidemias
Polymorphism
Point Mutation
Endoplasmic Reticulum
Screening
Proteins
Staining and Labeling
DNA

Keywords

  • Haplotype analysis
  • Low density lipoprotein receptor mutation
  • cDNA expression

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

Cite this

Identification and characterization of LDL receptor gene mutations in hyperlipidemic Chinese. / Chang, Jui Hung; Pan, Ju Pin; Tai, Der Yan; Huang, Ai Chun; Li, Pi Hung; Ho, Hui Ling; Hsieh, Hui Ling; Chou, Shiu Ching; Lin, Wen Lang; Lo, Eric; Chang, Ching Yu; Tseng, Jerming; Su, Ming Tsan; Lee-Chen, Guey Jen.

In: Journal of Lipid Research, Vol. 44, No. 10, 01.10.2003, p. 1850-1858.

Research output: Contribution to journalArticle

Chang, JH, Pan, JP, Tai, DY, Huang, AC, Li, PH, Ho, HL, Hsieh, HL, Chou, SC, Lin, WL, Lo, E, Chang, CY, Tseng, J, Su, MT & Lee-Chen, GJ 2003, 'Identification and characterization of LDL receptor gene mutations in hyperlipidemic Chinese', Journal of Lipid Research, vol. 44, no. 10, pp. 1850-1858. https://doi.org/10.1194/jlr.M200470-JLR200
Chang, Jui Hung ; Pan, Ju Pin ; Tai, Der Yan ; Huang, Ai Chun ; Li, Pi Hung ; Ho, Hui Ling ; Hsieh, Hui Ling ; Chou, Shiu Ching ; Lin, Wen Lang ; Lo, Eric ; Chang, Ching Yu ; Tseng, Jerming ; Su, Ming Tsan ; Lee-Chen, Guey Jen. / Identification and characterization of LDL receptor gene mutations in hyperlipidemic Chinese. In: Journal of Lipid Research. 2003 ; Vol. 44, No. 10. pp. 1850-1858.
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T1 - Identification and characterization of LDL receptor gene mutations in hyperlipidemic Chinese

AU - Chang, Jui Hung

AU - Pan, Ju Pin

AU - Tai, Der Yan

AU - Huang, Ai Chun

AU - Li, Pi Hung

AU - Ho, Hui Ling

AU - Hsieh, Hui Ling

AU - Chou, Shiu Ching

AU - Lin, Wen Lang

AU - Lo, Eric

AU - Chang, Ching Yu

AU - Tseng, Jerming

AU - Su, Ming Tsan

AU - Lee-Chen, Guey Jen

PY - 2003/10/1

Y1 - 2003/10/1

N2 - 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, 1402T, 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.

AB - 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, 1402T, 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.

KW - Haplotype analysis

KW - Low density lipoprotein receptor mutation

KW - cDNA expression

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