期刊
JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS
卷 17, 期 2, 页码 131-140出版社
JAPAN ATHEROSCLEROSIS SOC
DOI: 10.5551/jat.2873
关键词
Mutation; Autosomal recessive hypercholesterolemia; Phosphotyrosine-binding domain; SNPs
资金
- Program for the Promotion of Fundamental Studies on Health Science of the Japanese Organization for Pharmaceutical Safety and Research [MPJ-3]
- National Institute of Biomedical Innovation (NIBIO) of Japan [05-29]
Aim: The autosomal recessive hypercholesterolemia (ARH) gene is located on chromosome 1p35 and encodes a 308-amino acid protein containing a phosphotyrosine-binding domain. Several researchers have identified mutations of ARH that cause autosomal recessive hypercholesterolemia; however, it remains unknown whether this gene is involved in common hypercholesterolemia. Methods and Results: We searched for polymorphisms of the ARH gene by denaturing high-performance liquid chromatography and direct sequencing. We identified 18 single nucleotide polymorphisms of the gene, including 9 novel polymorphisms, and determined 2 haplotype blocks. No association was observed between common hypercholesterolemia and any polymorphisms or haplotypes of the ARH gene; however, we newly identified a rare Thr56Met missense mutation located in the phosphotyrosine-binding domain, which is the functional domain responsible for cholesterol metabolism. Among 1,800 Japanese individuals enrolled in the Suita study, only 4 were heterozygous for Thr56Met and all had hypercholesterolemia. The total cholesterol level and low-density lipoprotein cholesterol level of diabetic patients with the Thr56Met missense mutation was 276.3 +/- 13.8 mg/dL and 185.3 +/- 7.37 mg/dL, respectively. Conclusions: Because the Thr56Met missense mutation occurs in an orthologously conserved functional domain and all subjects with the mutation had hypercholesterolemia resembling familiar hypercholesterolemia, it may be a cause of familial hypercholesterolemia.
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