Ritter J K, Yeatman M T, Ferreira P, Owens I S
Human Genetics Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.
J Clin Invest. 1992 Jul;90(1):150-5. doi: 10.1172/JCI115829.
Patients with Crigler-Najjar syndrome (CN) type I inherit an autosomal recessive trait for hyperbilirubinemia, which is characterized by the total absence of bilirubin UDP-glucuronosyltransferase (transferase) activity. The recent identification of two bilirubin transferase isoforms with identical carboxyl termini (Ritter, J. K., J. M. Crawford, and I. S. Owens. 1991. J. Biol. Chem. 266:1043-1047) led to the discovery of a unique locus, UGT1, which encodes a family of UDP-glucuronosyltransferase isozymes, including the two bilirubin forms (Ritter, J. K., F. Chen, Y. Y. Sheen, H. M. Tran, S. Kimura, M. T. Yeatman, and I. S. Owens. 1992. J. Biol. Chem. 267:3257-3261). The UGT1 locus features a complex of six overlapping transcriptional units encoding transferases, each of which shares the four most 3' exons (2, 3, 4, and 5) specifying the 3' half of the transferase coding regions (condons 289-533) and the entire 3' untranslated region of each mRNA. This gene model predicts that a single critical mutation in any of these four "common" exons may inactivate the entire family of encoded transferases. In agreement with this prediction, we show here that in the first CN type I individual analyzed (patient F.B.), a 13-bp deletion has occurred in exon 2. Analysis of product generated by the polymerase chain reaction and genomic DNA demonstrated that F.B. is homozygous for the defective allele (UGT1*FB), and that the consanguineous parents are both heterozygotic at this locus. The mutation is predicted to result in the synthesis of severely truncated bilirubin transferase isozymes that are lacking a highly conserved sequence in the carboxyl-terminus and the characteristic membrane (endoplasmic reticulum)-anchoring segment of the protein molecule.
I型克里格勒-纳贾尔综合征（CN）患者遗传了一种常染色体隐性高胆红素血症性状，其特征是完全缺乏胆红素UDP-葡萄糖醛酸基转移酶（转移酶）活性。最近鉴定出两种具有相同羧基末端的胆红素转移酶同工型（里特，J.K.，J.M.克劳福德，和I.S.欧文斯。1991年。《生物化学杂志》266:1043 - 1047），从而发现了一个独特的基因座UGT1，它编码一个UDP-葡萄糖醛酸基转移酶同工酶家族，包括两种胆红素形式（里特，J.K.，F.陈，Y.Y.申，H.M.陈，S.木村，M.T.叶特曼，和I.S.欧文斯。1992年。《生物化学杂志》267:3257 - 3261）。UGT1基因座具有一个由六个重叠转录单位组成的复合体，这些转录单位编码转移酶，每个转录单位共享最3'端的四个外显子（2、3、4和5），这些外显子指定转移酶编码区的3'半部分（密码子289 - 533）以及每个mRNA的整个3'非翻译区。这个基因模型预测，这四个“共同”外显子中任何一个的单个关键突变可能会使整个编码转移酶家族失活。与这一预测一致，我们在此表明，在分析的首例I型CN个体（患者F.B.）中，外显子2发生了13个碱基对的缺失。对聚合酶链反应产生的产物和基因组DNA的分析表明，F.B.对于缺陷等位基因（UGT1*FB）是纯合的，并且近亲父母在该基因座均为杂合子。预计该突变会导致合成严重截短的胆红素转移酶同工酶，这些同工酶在羧基末端缺乏高度保守的序列以及蛋白质分子的特征性膜（内质网）锚定段。
