Functional analysis of low-density lipoprotein receptor in homozygous familial hypercholesterolemia patients with novel 1439 C→T mutation of low-density lipoprotein receptor gene

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Author:
LIN Jie(Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing 100029, China;Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China,Hengyang, Hunan 421001, China)
JIANG Zhi-sheng(Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China,Hengyang, Hunan 421001, China)
WANG Lu-ya(Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing 100029, China)
LIU Shu(Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing 100029, China)
XIA Jun-hui(Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China,Hengyang, Hunan 421001, China)
YONG Qiang(Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing 100029, China)
DU Lan-ping(Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing 100029, China)
PAN Xiao-dong(Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing 100029, China)
XUE Hong(Institute of Basic Medical Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005,China)
CHEN Bao-sheng(Institute of Basic Medical Science, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005,China)
Journal Title:
CHINESE MEDICAL JOURNAL
Issue:
Volume 121, Issue 09, 2008
DOI:
Key Word:
familial hypercholesterolemia; LDL receptor; gene mutation; gene function

Abstract: Background Familial hypercholesterolemia (FH), caused by low density lipoprotein (LDL) receptor (LDL-R) gene mutations, is associated with increased risk of premature coronary heart disease. Until now, limited molecular data concerning FH are available in China. The present study described the clinical profiles and cell biological defects of a Chinese FH kindred with novel LDL-R gene mutation.Methods The patient's LDL-R gene coding region was sequenced. The patient's lymphocytes were isolated and the LDL-R expression, binding and up-take functions were observed by immunohistochemistry staining and flow cytometry detection. The patient's heart and the major large vessels were detected by vessel ultrasound examination and myocardial perfusion imaging (MPI).Results The patient's LDL-R expression, LDL binding and up-take functions were significantly lower than normal control (39%, 63% and 76% respectively). A novel homozygous 1439 C→T mutation of the LDL-R gene was detected in the patient and his family. ECG showed atypical angina pectoris. Echocardiogram showed stenosis of the coronary artery and calcification of the aortic valve and its root. Blood vessel ultrasound examination showed the thickness of large vessel intima, and the vessel lumen was narrowed by 71%. MPI showed ischemic changes.Conclusions The LDL-R synthesis dysfunction of FH patients leads to arterial stenosis and calcification, which are the major phenotype of the clinical disorder. The mutation of the LDL-R gene is determined. These data increase the mutational spectrum of FH in China.

  • [1]Libby P,Ridker PM,Maseri A.Inflammation in atherosclerosis.Nature 2002; 420:868-874.
  • [2]Lusis AJ.Atherosclerosis.Nature 2000; 407:233-241.
  • [3]Dorsch MF,Lawrance RA,Durham NP,Hall AS.Familial hypercholesterolaemia is underdiagnosed after AMI.BMJ 2001; 322:111-117.
  • [4]Innerarity TL,Weisgraber KH,Arnold KS,Mahley RW,Krauss RM,Vega GL,et al.Familial defective apolipoprotein B-100:low density lipoproteins with abnormal receptor binding.Proc Nail Acad Sci USA 1987; 84:6919-6923.
  • [5]Abifadel M,Varret M,Rabès JP,Allard D,Ouguerram K,Devillers M,et al.Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.Nat Genet 2003; 34:154-156.
  • [6]Goldstein JL,Brown MS.Molecular medicine.The cholesterol quartet.Science 2001; 292:1310-1312.
  • [7]O'Rourke RA,Brundage BH,Froelicher VF,Greenland P,Grundy SM,Hachamovitch R,et al.American College of Cardiology/American Heart Association Expert Consensus document on electron-beam computed tomography for the diagnosis and prognosis of coronary artery disease.Circulation 2000; 102:126-140.
  • [8]O'Malley PG,Taylor AJ,Jackson JL,Doherty TM,Detrano RC.Prognostic value of coronary electron-beam computed tomography for coronary heart disease events in asymptomatic populations.Am J Cardiol 2000; 85:945-948.
  • [9]Doherty TM,Fitzpatrick LA,Inoue D,Qiao JH,Fishbein MC,Detrano RC.Molecular,endocrine,and genetic mechanisms of arterial calcification.Endocr Rev 2004; 25:629-672.
  • [10]Greenland P,LaBree L,Azen SP,Doherty TM,Detrano RC.Coronary artery calcium score combined with Framingham score for risk prediction in asymptomatic individuals.JAMA 2004; 291:210-215.
  • [11]Pimstone SN,Sun XM,du Souich C,Frohlich JJ,Hayden MR,Soutar AK.Pheotypic variation in heterozygous familial hepercholesterolemia.A comparison of Chinese patients with the same or similar mutations in the LDL receptor gene in China or Canada.Arterioscler Thromb Vasc Biol 1998; 18:309-315.
  • [12]Xie L,Gong QH,Xie ZG,Liang ZM,Hu ZM,Xia K,et al.Two novel mutations of the LDL receptor gene associated with familial hypercholesterolemia in a Chinese family.Chin Med J 2007; 19:1694-1699.
  • [13]Mak YT,Pang CP,Tomlinson B,Zhang J,Chan YS,Mak TW,et al.Mutations in the low-density lipoprotein receptor gene in Chinese familial hypercholesterolemia patients.Arterioscler Thromb Vasc Biol 1998; 18:1600-1605.
  • [14]Cai H,Fan L,Sun X,Chen Q.LDL receptor research in China.Chin Med J 1995; 108:177-182.
  • [15]Sun XM,Patel DD,Webb JC,Knight BL,Fan LM,Cai HJ,et al.Familial hypercholesterolemia in China.Identification of mutations in the LDL-receptor gene that result in a receptor-negative phenotype.Arterioscler Thromb 1994; 14:85-94.
  • [16]Sakai H,Kaneshige H,Endoh M.Determination of LDL receptors on cultured lymphocytes using fluorescein-labeled LDL.Am J Clin Pathol 1982; 78:58-62.
  • [17]Can S,Wang L,Qin Y,Lin J,Wu B,Liu S,et al.Analysis of low-density lipoprotein receptor gene mutations in a Chinese patient with clinically homozygous familial hypercholesterolemia.Chin Med J 2003; 16:1535-1538.
  • [18]Ellis SM,Naoumova RP,Neuwirth CK,Eckersley R,Cosgrove DO,Thompson GR,et al.Measurement of the reflectivity of the intima-medial layer of the common carotid artery improves the discriminatory value of intima-medial thickness measurement as a predictor of risk of atherosclerotic disease.Ultrasound Med Biol 2007; 33:1029-1038.
  • [19]Schmidt HH,Hill S,Makariou EV,Feuerstein IM,Dugi KA,Hoeg JM.Relation of cholesterol-year score to severity of calcific atherosclerosis and tissue deposition in homozygous familial hypercholesterolemia.Am J Cardiol 1996; 77:575-580.
  • [20]Hussain MM.Structural,biochemical and signaling properties of the low-density lipoprotein receptor gene family.Front Biosci 2001; 6:417-428.
  • [21]Rudenko G,Henry L,Henderson K,Ichtchenko K,Brown MS,Goldstein JL,et al.Structure of the LDL receptor extracellular domain at endosomal pH.Science 2002; 298:2353-2358.
  • [22]Nguyen AT,Hirama T,Chauhan V,Mackenzie R,Milne R.Binding characteristics of a panel of monoclonal antibodies against the ligand binding domain of the human LDLr.J Lipid Res 2006; 47:1399-1405.
  • [23]Rudenko {3,Deisenhofer J.The low-density lipoprotein receptor:ligands,debates and lore.Curr Opin Struct Biol 2003;13:683-689.
  • [24]Ye ZX,Cheng HM,Chiou KR,Huang PH,Lin S J,Charng MJ.Relation of coronary artery calcium to flow-mediated dilation and C-reactive protein levels in asymptomatic patients with heterozygous familial hypercholesterolemia.Am J Cardiol 2007; 100:1119-1123.
  • [25]Ellis SM,Naoumova RP,Neuwirth CK,Eckersley R,Cosgrove DO,Thompson GR,et al.Measurement of the reflectivity of the intima-medial layer of the common carotid artery improves the discriminatory value of intima-medial thickness measurement as a predictor of risk of atherosclerotic disease.Ultrasound Med Biol 2007; 33:1029-1038.
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