IDENTIFICATION OF DEFECT IN THE GENES FOR BILIRUBIN UDP-GLUCURONOSYL-TRANSFERASE IN A PATIENT WITH CRIGLER-NAJJAR SYNDROME TYPE-II
IDENTIFICATION OF DEFECT IN THE GENES FOR BILIRUBIN UDP-GLUCURONOSYL-TRANSFERASE IN A PATIENT WITH CRIGLER-NAJJAR SYNDROME TYPE-II
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DOI：
10.1006/bbrc.1993.2610
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发表时间：
1993-12-30
影响因子：
3.1
通讯作者：
KOIWAI, O
中科院分区：
文献类型：
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作者：
AONO, S;YAMADA, Y;KOIWAI, O
Crigler-Najjar综合征（CN）II型的特征是由于肝胆红素UDP-葡萄糖醛酸基转移酶（UGT）活性降低导致的重度慢性非溶血性非结合型高胆红素血症。已鉴定出两种胆红素UGT同工酶，UGT 1A和UDT 1D。我们分析了一个5岁的日本男性CN II型患者的胆红素UGT基因的DNA序列，该患者的父母是近亲。在UGT 1A和UGT 1D基因的外显子I上发现点突变。异常分别是UGT 1A cDNA的碱基位置211处的G被A和UGT 1D的碱基位置395处的T被C的单核苷酸取代。我们发现另一个单核苷酸替换T由G外显子5共同的两个基因在碱基位置1456的UGT 1A cDNA或1459的UGT 1D cDNA。这三个突变分别导致UGT 1A蛋白的氨基酸位置71和486处的甘氨酸变为精氨酸和酪氨酸变为天冬氨酸，以及UGT 1D蛋白的氨基酸位置132和487处的亮氨酸变为脯氨酸和酪氨酸变为天冬氨酸。我们的病人是纯合子的所有缺陷和他的父母和哥哥是杂合子的所有缺陷等位基因。研究结果表明，CN II型是作为常染色体隐性遗传性状遗传的。
Crigler-Najjar syndrome (CN) type II is characterized by severe chronic nonhemolytic unconjugated hyperbilirubinemia due to reduced hepatic bilirubin UDP-glucuronosyltransferase (UGT) activity. Two bilirubin UGT isozymes, UGT1A and UDT1D, have been identified. We analyzed the DNA sequence of the bilirubin UGT genes in a 5-year-old Japanese male patient with CN type II, who had consanguineous parents. Point mutations were found on exons I of the UGT1A and UGT1D genes. The abnormalities were single nucleotide substitutions of G by A and of T by C at base position 211 of UGT1A cDNA and at base position 395 of the UGT1D, respectively. We found another single nucleotide substitution of T by G on exon 5 common to both genes at base position 1456 of the UGT1A cDNA or 1459 of the UGT1D cDNA. These three mutations result in changes of glycine to arginine and of tyrosine to aspartic acid at amino acid positions 71 and 486 of the UGT1A protein, and of leucine to proline and of tyrosine to aspartic acid at amino acid positions 132 and 487 of the UGT1D protein, respectively. Our patient was homozygous for all defects and his parents and elder brother were heterozygous for all defective alleles. The findings suggest that the CN Type II is inherited as an autosomal recessive trait.