A novel Thr56Met mutation of the autosomal recessive hypercholesterolemia gene associated with hypercholesterolemia

Koji Harada, Yoshihiro Miyamoto, Hiroko Morisaki, Naotaka Ohta, Itaru Yamanaka, Yoshihiro Kokubo, Hisashi Makino, Mariko Harada-Shiba, Akira Okayama, Hitonobu Tomoike, Okamura Tomonori, Yoshihiko Saito, Yasunao Yoshimasa, Takayuki Morisaki

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)131-140
Number of pages10
JournalJournal of atherosclerosis and thrombosis
Issue number2
Publication statusPublished - 2010
Externally publishedYes


  • Autosomal recessive hypercholesterolemia
  • Mutation
  • Phosphotyrosine-binding domain
  • SNPs

ASJC Scopus subject areas

  • Internal Medicine
  • Cardiology and Cardiovascular Medicine
  • Biochemistry, medical


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