THE RESEARCH FOR DEVELOPMENT OF GENETHERAPY AND PORPHYRIN-THERAPY FORNEONATAL HYPERBILIRUBINEMIA

我们调查了Crigler-Najjar综合征（CN）I型患者胆红素UGT基因的新型缺陷。该突变是一个单核苷酸取代，该突变导致终止密码子。患者为该缺陷的纯合子，而其非血亲的父母临床上正常，为该缺陷等位基因的杂合子。我们对Ⅱ型CN患者的胆红素UGT基因进行了CN序列分析，发现了3个点突变。异常是单核苷酸取代。这三个突变导致胆红素UGT蛋白的氨基酸改变。我们的病人是这种缺陷的纯合子，他的父母和哥哥是有缺陷的等位基因的杂合子。研究结果表明，CN II型是作为一种常染色体隐性遗传性状遗传。我们分析了9例吉尔伯特综合征（GS）患者的遗传背景。对胆红素UGT基因的6种点突变进行了研究。每个病人都是点突变的杂合子。注射锡原卟啉（SnPP）和光照射的组合产生了血清葡萄糖水平的急性下降，并与神经系统症状，血压变化和最终死亡的反应。在体内和体外肝细胞中研究了芳基硫酸酯酶从溶酶体中的释放。L-抗坏血酸被认为是最有效的保护SnPP处理的大鼠免受光毒性。治疗后生存期明显延长，异常行为发生率降低。钴-中卟啉抑制大鼠脾血红素氧合酶的活性，但几乎不刺激脂质过氧化。钴-中卟啉可能是新生儿高胆红素血症化学预防的一个有希望的候选物。

We investigate new type of defect in the gene for bilirubin UGT in patient with Crigler-Najjar syndrome (CN) type I.This mutation is a single nucleotide substitution, and this mutation results in a stop codon. The patient is homozygous for the defect, and his nonconsanguineous parents, who are clinically normal, are heterozygous for the defective allele. We analyzed the CN sequeuce of the bilirubin UGT genes in patient with CN type II.Three point mutations were found on the genes. The abnormalities were single nucleotide substitutions. These three mutations result in changes of amino acid of the bilirubin UGT protein. Our patient was homozygous for this defects and his parents and elder brother were heterozygous for the defective alleles. The findings suggest that the CN type II is inherited as an autosomal recessive trait. We analyzed the genetic background of nine patients with Gilbert's syndrome (GS). Six kinds of point mutations were investigated in bilirubin UGT gene. Each patient was heterozygous for a point mutation.The combination of injection of tin-protoporphyrin (SnPP) and photoirradiaiton produced an acute decrease in serum glucose levels and reacted with neurological signs, changes in blood pressure and eventual death. The release of arylsulfatase from lysosome was investigated in hepatocytes in vivo and in vitro. L-ascorbic acid was found to be most effective in protecting SnPP-treated rats against phototoxiocity. The survival period was markedly prolonged, and the frequency of abnormal behaviors was reduced with the treatment. Cobalt-mesoporphyrin inhibited the activity of rat splenic heme oxygenase but scarcely stimulated peroxidation of lipids. Cobalt-mesoporphyrin may be a promising candidate for a chemopreventive of neonatal hyperbilirubinemia.