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

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.