A novel Thr56Met mutation of the autosomal recessive hypercholesterolemia gene associated with hypercholesterolemia.
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.
Harada
Koji
K
Department of Atherosclerosis and Diabetes, National Cardiovascular Center, Osaka, Japan.
Miyamoto
Yoshihiro
Y
Morisaki
Hiroko
H
Ohta
Naotaka
N
Yamanaka
Itaru
I
Kokubo
Yoshihiro
Y
Makino
Hisashi
H
Harada-Shiba
Mariko
M
Okayama
Akira
A
Tomoike
Hitonobu
H
Okamura
Tomonori
T
Tomonori
Okamura
O
Saito
Yoshihiko
Y
Yoshimasa
Yasunao
Y
Morisaki
Takayuki
T
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
D048868:Adaptor Proteins, Signal Transducing; D008078:Cholesterol, LDL; C469745:LDLRAP1 protein, human; D019000:Phosphotyrosine; D013912:Threonine; D002784:Cholesterol; D008715:Methionine