POINT MUTATIONS IN THE TYROSINE AMINOTRANSFERASE GENE IN TYROSINEMIA TYPE-II
POINT MUTATIONS IN THE TYROSINE AMINOTRANSFERASE GENE IN TYROSINEMIA TYPE-II
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DOI：
10.1073/pnas.89.19.9297
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发表时间：
1992-10-01
影响因子：
11.1
通讯作者：
SCHERER, G
中科院分区：
文献类型：
--
作者：
NATT, E;KIDA, K;SCHERER, G
II型酪氨酸血症（Richner-Hanhart综合征，RHS）是一种常染色体隐性遗传疾病，其特征为角膜炎、掌跖角化过度、智力低下和血液酪氨酸水平升高。该疾病是由于肝酪氨酸转氨酶（TAT；L-酪氨酸：2-酮戊二酸转氨酶，EC 2.6.1.5）缺乏所致，这是一种由 12 个外显子基因编码的 454 个氨基酸的蛋白质。为了鉴定从三名 RHS 患者克隆的 5 个 TAT 等位基因中的致病突变，测试了由正常和突变 TAT 等位基因构建的嵌合基因在瞬时表达测定中指导 TAT 活性的情况。对被确定为无功能的区域的 DNA 序列分析揭示了六种不同的点突变。三个 RHS 等位基因分别在密码子 57、223 和 417 处有无义突变。一个“复杂”RHS 等位基因在内含子 8 中携带 GT --> GG 剪接供体突变，以及氨基酸 362 处的 Gly --> Val 取代。第五个 RHS 等位基因的内含子 2 中的新剪接受体位点导致阅读框发生变化。
Tyrosinemia type II (Richner-Hanhart syndrome, RHS) is a disease of autosomal recessive inheritance characterized by keratitis, palmoplantar hyperkeratosis, mental retardation, and elevated blood tyrosine levels. The disease results from deficiency in hepatic tyrosine aminotransferase (TAT; L-tyrosine:2-oxoglutarate aminotransferase, EC 2.6.1.5), a 454-amino acid protein encoded by a gene with 12 exons. To identify the causative mutations in five TAT alleles cloned from three RHS patients, chimeric genes constructed from normal and mutant TAT alleles were tested in directing TAT activity in a transient expression assay. DNA sequence analysis of the regions identified as nonfunctional revealed six different point mutations. Three RHS alleles have nonsense mutations at codons 57, 223, and 417, respectively. One "complex" RHS allele carries a GT --> GG splice donor mutation in intron 8 together with a Gly --> Val substitution at amino acid 362. A new splice acceptor site in intron 2 of the fifth RHS allele leads to a shift in reading frame.