Imoto S, Tanizawa Y, Sato Y, Kaku K, Oka Y
Third Department of Internal Medicine, Yamaguchi University School of Medicine, Japan.
Br J Haematol. 1996 Jul;94(1):191-7. doi: 10.1046/j.1365-2141.1996.d01-1771.x.
Erythropoietic protoporphyria (EPP) is a hereditary disorder caused by mutations of the ferrochelatase gene. We investigated a Japanese patient with a dominant form of erythropoietic protoporphyria for a ferrochelatase mutation. Sequence analysis of the proband's ferrochelatase cDNA revealed a T to C point mutation at nucleotide 557. This mutation resulted in the replacement of Ile by Thr at amino acid position 186, a novel mutation in erythropoietic protoporphyria. An increase in ferrochelatase activity was not observed in the crude extract of E. coli over-expressing the mutant protein compared with the control, whereas a marked increase in activity was observed in that over-expressing the wild type. Prediction of the secondary structure of ferrochelatase suggested that the Ile186-->Thr mutation changed the original beta-sheet structure to an alpha helix in the region including amino acid residue of mutation. We conclude that, in the patient, the Ile186-->Thr mutation had abolished enzyme activity, possibly by disrupting the secondary structure, thereby causing erythropoietic protoporphyria.
红细胞生成性原卟啉病（EPP）是一种由亚铁螯合酶基因突变引起的遗传性疾病。我们对一名患有显性红细胞生成性原卟啉病的日本患者进行了亚铁螯合酶突变研究。对先证者的亚铁螯合酶cDNA进行序列分析，发现核苷酸557处存在T到C的点突变。该突变导致氨基酸位置186处的异亮氨酸被苏氨酸取代，这是红细胞生成性原卟啉病中的一种新突变。与对照相比，在过表达突变蛋白的大肠杆菌粗提物中未观察到亚铁螯合酶活性增加，而在过表达野生型的粗提物中观察到活性显著增加。亚铁螯合酶二级结构预测表明，Ile186→Thr突变在包括突变氨基酸残基的区域将原来的β折叠结构改变为α螺旋。我们得出结论，在该患者中，Ile186→Thr突变可能通过破坏二级结构而使酶活性丧失，从而导致红细胞生成性原卟啉病。
