Polymorphism in the promoter and coding regions of human metallothionein IIA gene

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Cadmium concentration in the human tissues increase with aging because most of the accumulated cadmium may be remained in the bodies without excreting. General Japanese usually well eat rice which naturally containing relatively high concentration of cadmium. On the other hand, cadmium has been known to induce synthesis of metallothionein, a mental binding protein which reduces toxicity of heavy metals. In the general adults, most of cadmium accumulated in the tissues exist as low toxic complex with matallothionein. We found some Japanese adults whose kidneys have relatively low concentration of metallothionein. There is a possibility that the "low metallothionein" may be induced by genetic disorder. Therefore, we examined abnormality of nucleotide sequence of metallothionein gene and its promoter region of general Japanese by single-stranded conformation polymorphism method(PCR-SSCP). Genomic DNA samples were extracted from cortex of kidney of the forensic autopsy samples(21 examples). By PCR-SSCP and direct sequencing methods, abnormalities of nucleotide sequence of metallothionein gene and its promoter region were observed in some samples. Single base substitutions were found in the promoter region of four samples and in the exon 3 of two samples. The substitution(A->G) in the promoter region in all four samples was observed in 5 bases upstream from the transcription starting point. On the other hand, the mutation(GCC->GTC) of exon 3 was observed in the same site of the two samples, inducing the amino acid substitution of Ala->Val. In one sample, these two substitutions was observed in identical allele of promoter and exon 3. Effect of these base substitutions on the synthesis of metallothionein will be examined in future.