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

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.

• Authors: Koji Harada, Yoshihiro Miyamoto, Hiroko Morisaki, Naotaka Ohta, Itaru Yamanaka, Yoshihiro Kokubo, Hisashi Makino, Mariko Harada-Shiba, Akira Okayama, Hitonobu Tomoike, Tomonori Okamura, Okamura Tomonori, Yoshihiko Saito, Yasunao Yoshimasa, Takayuki Morisaki
• Journal: Journal of atherosclerosis and thrombosis (J Atheroscler Thromb) Vol. 17 Issue 2 Pg. 131-40 (Feb 26 2010) ISSN: 1880-3873 [Electronic] Japan
• PMID: 20124734 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Cholesterol, LDL
• LDLRAP1 protein, human
• Phosphotyrosine
• Threonine
• Cholesterol
• Methionine

Topics

• Adaptor Proteins, Signal Transducing (genetics, physiology)
• Alleles
• Cholesterol (metabolism)
• Cholesterol, LDL (metabolism)
• Chromatography, High Pressure Liquid (methods)
• Genes, Recessive
• Haplotypes
• Heterozygote
• Humans
• Hypercholesterolemia (genetics)
• Japan
• Methionine (genetics)
• Models, Genetic
• Mutation
• Phosphotyrosine (chemistry)
• Polymorphism, Genetic
• Protein Structure, Tertiary
• Threonine (genetics)