title: A novel Thr56Met mutation of the autosomal recessive hypercholesterolemia gene associated with hypercholesterolemia.
abstract: OBJECTIVE
  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.
  
  
  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.affiliation: Department of Atherosclerosis and Diabetes, National Cardiovascular Center, Osaka, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Harada
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Hiroko
authors.initials: H
authors.lastname: Morisaki
authors.forename: Naotaka
authors.initials: N
authors.lastname: Ohta
authors.forename: Itaru
authors.initials: I
authors.lastname: Yamanaka
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kokubo
authors.forename: Hisashi
authors.initials: H
authors.lastname: Makino
authors.forename: Mariko
authors.initials: M
authors.lastname: Harada-Shiba
authors.forename: Akira
authors.initials: A
authors.lastname: Okayama
authors.forename: Hitonobu
authors.initials: H
authors.lastname: Tomoike
authors.forename: Tomonori
authors.initials: T
authors.lastname: Okamura
authors.forename: Okamura
authors.initials: O
authors.lastname: Tomonori
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Saito
authors.forename: Yasunao
authors.initials: Y
authors.lastname: Yoshimasa
authors.forename: Takayuki
authors.initials: T
authors.lastname: Morisaki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000502:physiology*; D000483:Alleles; D002784:Cholesterol / Q000378:metabolism; D008078:Cholesterol, LDL / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D005808:Genes, Recessive; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics*; D007564:Japan; D008715:Methionine / Q000235:genetics; D008957:Models, Genetic; D009154:Mutation; D019000:Phosphotyrosine / Q000737:chemistry; D011110:Polymorphism, Genetic; D017434:Protein Structure, Tertiary; D013912:Threonine / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008078:Cholesterol, LDL; C469745:LDLRAP1 protein, human; D019000:Phosphotyrosine; D013912:Threonine; D002784:Cholesterol; D008715:Methionine