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, Tomonori Okamura, Yoshihiko Saito, Yasunao Yoshimasa, Takayuki Morisaki

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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
Volume17
Issue number2
Publication statusPublished - 2010
Externally publishedYes

Fingerprint

Recessive Genes
Hypercholesterolemia
Polymorphism
Genes
Missense Mutation
Mutation
Phosphotyrosine
Haplotypes
Cholesterol
Hyperlipoproteinemia Type II
High performance liquid chromatography
Chromosomes
Metabolism
LDL Cholesterol
Single Nucleotide Polymorphism
Nucleotides
High Pressure Liquid Chromatography
Research Personnel
Autosomal Recessive Hypercholesterolemia
Association reactions

Keywords

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

ASJC Scopus subject areas

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

Cite this

Harada, K., Miyamoto, Y., Morisaki, H., Ohta, N., Yamanaka, I., Kokubo, Y., ... Morisaki, T. (2010). A novel Thr56Met mutation of the autosomal recessive hypercholesterolemia gene associated with hypercholesterolemia. Journal of Atherosclerosis and Thrombosis, 17(2), 131-140.

A novel Thr56Met mutation of the autosomal recessive hypercholesterolemia gene associated with hypercholesterolemia. / Harada, Koji; Miyamoto, Yoshihiro; Morisaki, Hiroko; Ohta, Naotaka; Yamanaka, Itaru; Kokubo, Yoshihiro; Makino, Hisashi; Harada-Shiba, Mariko; Okayama, Akira; Tomoike, Hitonobu; Okamura, Tomonori; Saito, Yoshihiko; Yoshimasa, Yasunao; Morisaki, Takayuki.

In: Journal of Atherosclerosis and Thrombosis, Vol. 17, No. 2, 2010, p. 131-140.

Research output: Contribution to journalArticle

Harada, K, Miyamoto, Y, Morisaki, H, Ohta, N, Yamanaka, I, Kokubo, Y, Makino, H, Harada-Shiba, M, Okayama, A, Tomoike, H, Okamura, T, Saito, Y, Yoshimasa, Y & Morisaki, T 2010, 'A novel Thr56Met mutation of the autosomal recessive hypercholesterolemia gene associated with hypercholesterolemia', Journal of Atherosclerosis and Thrombosis, vol. 17, no. 2, pp. 131-140.
Harada, Koji ; Miyamoto, Yoshihiro ; Morisaki, Hiroko ; Ohta, Naotaka ; Yamanaka, Itaru ; Kokubo, Yoshihiro ; Makino, Hisashi ; Harada-Shiba, Mariko ; Okayama, Akira ; Tomoike, Hitonobu ; Okamura, Tomonori ; Saito, Yoshihiko ; Yoshimasa, Yasunao ; Morisaki, Takayuki. / A novel Thr56Met mutation of the autosomal recessive hypercholesterolemia gene associated with hypercholesterolemia. In: Journal of Atherosclerosis and Thrombosis. 2010 ; Vol. 17, No. 2. pp. 131-140.
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AU - Harada, Koji

AU - Miyamoto, Yoshihiro

AU - Morisaki, Hiroko

AU - Ohta, Naotaka

AU - Yamanaka, Itaru

AU - Kokubo, Yoshihiro

AU - Makino, Hisashi

AU - Harada-Shiba, Mariko

AU - Okayama, Akira

AU - Tomoike, Hitonobu

AU - Okamura, Tomonori

AU - Saito, Yoshihiko

AU - Yoshimasa, Yasunao

AU - Morisaki, Takayuki

PY - 2010

Y1 - 2010

N2 - 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.

AB - 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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KW - SNPs

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