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

J Atheroscler Thromb. 2010 Feb 26;17(2):131-40. doi: 10.5551/jat.2873. Epub 2010 Feb 3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / 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

Substances

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