Shady Amr A, Colby Brandon R, Cunha Luis F, Astrin Kenneth H, Bishop David F, Desnick Robert J
Department of Human Genetics, Mount Sinai School of Medicine, New York University, Fifth Avenue at 100th Street, New York, NY 10029, USA.
Br J Haematol. 2002 Jun;117(4):980-7. doi: 10.1046/j.1365-2141.2002.03558.x.
Mutations in the uroporphyrinogen III synthase (URO-synthase) gene cause congenital erythropoietic porphyria (CEP), an autosomal recessive inborn error of haem biosynthesis. Molecular analysis of the URO-synthase gene in seven unrelated CEP patients revealed eight novel mutations. These included four missense mutations (A69T, E81D, G188W and I219S), a deletion (21delG), two insertions (398insG and 672ins28) and one complex mutation (627del6ins39), as well as three previously reported mutations, C73R, T228M, and -86C-->A. When the four novel missense mutations were expressed in Escherichia coli, only E81D expressed significant enzymatic activity (30% of expressed wild-type activity), which was thermolabile. In addition, reverse transcription polymerase chain reaction studies demonstrated that E81D, which altered the penultimate nucleotide in exon 4, impaired splicing and caused about 85% exon 4 skipping. The identification and expression of these mutations provided genotype-phenotype correlations and further evidence of the molecular heterogeneity underlying this erythropoietic porphyria.
尿卟啉原III合酶（URO合酶）基因突变会导致先天性红细胞生成性卟啉病（CEP），这是一种常染色体隐性遗传的血红素生物合成先天性缺陷疾病。对7名无亲缘关系的CEP患者的URO合酶基因进行分子分析，发现了8种新突变。这些突变包括4种错义突变（A69T、E81D、G188W和I219S）、1种缺失突变（21delG）、2种插入突变（398insG和672ins28）和1种复合突变（627del6ins39），以及3种先前报道的突变C73R、T228M和-86C→A。当4种新的错义突变在大肠杆菌中表达时，只有E81D表现出显著的酶活性（为表达的野生型活性的30%），且该活性不耐热。此外，逆转录聚合酶链反应研究表明，改变外显子4倒数第二个核苷酸的E81D会损害剪接，并导致约85%的外显子4跳跃。这些突变的鉴定和表达提供了基因型与表型的相关性，并为这种红细胞生成性卟啉病潜在的分子异质性提供了进一步证据。
