title: Mutations in the LDL receptor gene in four Chinese homozygous familial hypercholesterolemia phenotype patients.
abstract: OBJECTIVE
  Familial hypercholesterolemia (FH) is an autosomal dominant disorder of lipoprotein metabolism caused by mutations in the low-density lipoprotein receptor (LDL-R) gene, leading to elevated levels of cholesterol and an increased risk of coronary heart disease. In this article, from four homozygous FH phenotype probands we identified disease causing mutations and analyzed the relationship between genotype and phenotype.
  
  
  RESULTS
  DNA sequencing identified five LDL-R point mutations in four unrelated families. We found a novel homozygous mutation (C210R), a homozygous mutation at W462X, a compound heterozygous mutation of C122Y and T383I, and a G>A intron 3 splice site homozygous mutation. The functional alteration caused by the novel C210R mutation was confirmed by FACS analysis. Four probands have high low-density lipoprotein cholesterol (LDL-C) levels, ranging from 14.65 to 27.66 mmol/L. Their heterozygous parents had relatively low levels. B-mode ultrasound supplemented by Doppler was used to examine aortic/mitral valve structural alterations and carotid intima-media thickness (ITM) in all probands. The ITM values were between 1.2 and 2.3mm, much higher than the normal value of <0.8mm.
  
  
  CONCLUSIONS
  Our data demonstrated that all the probands were associated with severe hypercholesterolemia, thick carotid IMT and a low CFVR (coronary flow velocity reserve) value. The novel mutation (C120Y) is a disease causing mutation.
authors.affiliation: Department of Atherosclerosis, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Affiliated of Capital University of Medical Sciences, Beijing 100029, PR China. wangluya@126.com
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: J
authors.initials: J
authors.lastname: Lin
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.forename: S
authors.initials: S
authors.lastname: Cao
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: Q
authors.initials: Q
authors.lastname: Yong
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.forename: B
authors.initials: B
authors.lastname: Wu
authors.forename: X
authors.initials: X
authors.lastname: Pan
authors.forename: L
authors.initials: L
authors.lastname: Du
authors.forename: C
authors.initials: C
authors.lastname: Wu
authors.forename: Y
authors.initials: Y
authors.lastname: Qin
authors.forename: B
authors.initials: B
authors.lastname: Chen
mesh_terms: D000293:Adolescent; D000328:Adult; D001021:Aortic Valve / Q000000981:diagnostic imaging; D044466:Asian People / Q000235:genetics; D002339:Carotid Arteries / Q000000981:diagnostic imaging; D002460:Cell Line; D002681:China; D008078:Cholesterol, LDL / Q000097:blood; D003326:Coronary Circulation; D004252:DNA Mutational Analysis; D015150:Echocardiography, Doppler; D005260:Female; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000000981:diagnostic imaging / Q000208:ethnology / Q000235:genetics*; D007438:Introns; D008297:Male; D008943:Mitral Valve / Q000000981:diagnostic imaging; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D022821:RNA Splice Sites; D011973:Receptors, LDL / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D017539:Tunica Intima / Q000000981:diagnostic imaging; D017540:Tunica Media / Q000000981:diagnostic imaging; D015854:Up-Regulation
chemical_list: D008078:Cholesterol, LDL; D022821:RNA Splice Sites; D011973:Receptors, LDL