Bloomer J, Bruzzone C, Zhu L, Scarlett Y, Magness S, Brenner D
Liver Center at The University of Alabama at Birmingham, Birmingham, Alabama 35294-0005, USA.
J Clin Invest. 1998 Jul 1;102(1):107-14. doi: 10.1172/JCI1347.
Protoporphyria is a genetic disorder in which a deficiency of mitochondrial ferrochelatase activity causes accumulation of protoporphyrin that produces severe liver damage in some patients. In this study, mutations of the ferrochelatase gene were examined in eight unrelated patients who had liver transplantation. RNA was prepared from liver and/ or lymphoblasts, and specific reverse transcriptase-nested polymerase chain reactions amplified and sequenced ferrochelatase cDNAs. Products shorter than normal resulted from an exon 3 deletion in three patients, exon 10 deletion in two, exon 2 deletion in one, and deletion of five nucleotides in exon 5 in one. Sequence of normal-size products revealed no other mutations. Western blot showed a reduced quantity of normal-size ferrochelatase protein in protoporphyria liver compared with normal liver (19-51%, mean 32% of normal). Levels of the mitochondrial protein F1-ATPase beta-subunit were not decreased to a similar degree. Liver ferrochelatase activity was reduced more than could be explained by the decrease in ferrochelatase protein (4-20%, mean 9% of normal). These results establish genetic heterogeneity in the most severe phenotype of protoporphyria. However, the gene mutations found share the property of causing a major structural alteration in the ferrochelatase protein.
原卟啉症是一种遗传性疾病，线粒体铁螯合酶活性缺乏导致原卟啉积累，在一些患者中会造成严重的肝脏损伤。在本研究中，对8例接受肝移植的非亲缘关系患者的铁螯合酶基因突变进行了检测。从肝脏和/或淋巴母细胞中提取RNA，通过特异性逆转录-巢式聚合酶链反应扩增并测序铁螯合酶cDNA。3例患者因外显子3缺失、2例因外显子10缺失、1例因外显子2缺失以及1例因外显子5缺失5个核苷酸而产生比正常产物短的片段。正常大小产物的序列未发现其他突变。蛋白质免疫印迹显示，与正常肝脏相比，原卟啉症肝脏中正常大小的铁螯合酶蛋白量减少（为正常的19% - 51%，平均为正常的32%）。线粒体蛋白F1 - ATP酶β亚基的水平没有下降到类似程度。肝脏铁螯合酶活性的降低幅度超过了铁螯合酶蛋白减少所能解释的范围（为正常的4% - 20%，平均为正常的9%）。这些结果证实了原卟啉症最严重表型存在遗传异质性。然而，所发现的基因突变都具有导致铁螯合酶蛋白发生重大结构改变的特性。
