Mutations in the LDL receptor gene in four Chinese homozygous familial hypercholesterolemia phenotype patients
Received 13 April 2008; received in revised form 13 July 2008; accepted 14 July 2008. published online 15 December 2008.
Abstract
Background and aims
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.
Methods and 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 27.66mmol/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.
Conclusion
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.
aDepartment 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
bInstitute of Cardiovascular Disease, Key Laboratory for Arteriosclerosis of Hunan Province, University of South China, Hengyang 421001, PR China
cDepartment of Biochemistry, China Academy of Medical Science, Beijing 100005, PR China
ABSTRACT