Identification of 16 novel mutations in the arglininosuccinate synthetase gene and genotype-phenotype correlation in 38 classical citrullinemia patients
Identification of 16 novel mutations in the arglininosuccinate synthetase gene and genotype-phenotype correlation in 38 classical citrullinemia patients
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DOI：
10.1002/humu.10230
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发表时间：
2003-07-01
期刊：
影响因子：
3.9
通讯作者：
Saheki, T
中科院分区：
文献类型：
--
作者：
Gao, HZ;Kobayashi, K;Saheki, T
经典型瓜氨酸血症（CTLN 1）是一种罕见的常染色体隐性遗传病，由位于染色体9q34.1上的氨基琥珀酸合成酶（ASS）基因突变引起。ASS在尿素循环中起限速酶的作用。此前，我们在CTLN 1患者的ASS基因中发现了32种突变，主要发生在日本和美国，迄今为止，在全球50个家族中描述了34种不同的突变。在本研究中，我们报告ASS突变检测到的35个额外的CTLN 1家庭从II国家。通过使用RT-PCR和/或基因组DNA-PCR分析ASS基因的整个编码序列和内含子-外显子边界，我们已经确定了16个新的突变（两个不同的1-bp缺失，一个67-bp插入和13个错义），并检测到12个已知突变。总共，在85个CTLN 1家族中鉴定出50种不同的突变（7种缺失，3种剪接位点，1种重复，2种无义和37种错义）。在一级序列与E. coli ASS蛋白的突变，可以得出结论，在30个不同位置发现的37个错义突变中的任何一个都导致人ASS蛋白的结构和功能损伤。已经发现有三种突变特别频繁：23个家族中的IVS 6 -2A>G（日本：20个，韩国：3个），18个家族中的G390 R（土耳其：6个，美国：5个，西班牙：3个，以色列：1个，奥地利：1个，加拿大：1个，和玻利维亚：1个），和R304 W在10个家庭（日本：9个和土耳其：1个）。ASS基因的大多数突变是“私有的”，分布在整个基因中，除了外显子5和12-14。截短突变或G390 R突变患者的临床病程似乎是早发性/重度。具有某些错义突变（G362 V或W179 R）的患者的表型更晚发/轻度。8例携带R86 H、A118 T、R265 H或K310 R突变的患者为成人/晚发型，其中4例在妊娠或产后表现出严重症状。然而，仍然很难证明基因型-表型相关性，因为许多患者是复合杂合子（具有两种不同的突变），在诊断时生活在不同的环境中，和/或有几种治疗方案或对疾病的各种知识。(C)2003 Wiley-Liss，Inc.
Classical citrullinemia (CTLN1), a rare autosomal recessive disorder, is caused by mutations of the argininosuccinate synthetase (ASS) gene, localized on chromosome 9q34.1. ASS functions as a rate,limiting enzyme in the urea cycle. Previously, we identified 32 mutations in the ASS gene of CTLN1 patients mainly in Japan and the United States, and to date 34 different mutations have been described in 50 families worldwide. In the present study, we report ASS mutations detected in 35 additional CTLN1 families from I I countries. By analyzing the entire coding sequence and the intron-exon boundaries of the ASS gene using RT-PCR and/or genomic DNA-PCR, we have identified 16 novel mutations (two different 1-bp deletions, a 67-bp insertion, and 13 missense) and have detected 12 known mutations. Altogether, 50 different mutations (seven deletion, three splice site, one duplication, two nonsense, and 37 missense) in 85 CTLN1 families were identified. On the basis of primary sequence comparisons with the crystal structure of E. coli ASS protein, it may be concluded that any of the 37 missense mutations found at 30 different positions led to structural and functional impairments of the human ASS protein. It has been found that three mutations are particularly frequent: IVS6-2A>G in 23 families (Japan: 20 and Korea: three), G390R in 18 families (Turkey: six, U.S.: five, Spain: three, Israel: one, Austria: one, Canada: one, and Bolivia: one), and R304W in 10 families (Japan: nine and Turkey: one). Most mutations of the ASS gene are "private" and are distributed throughout the gene, except for exons 5 and 12-14. It seems that the clinical course of the patients with truncated mutations or the G390R mutation is early onset/severe. The phenotype of the patients with certain missense mutations (G362V or W179R) is more late-onset/mild. Eight patients with R86H, A118T, R265H, or K310R mutations were adult/late-onset and four of them showed severe symptoms during pregnancy or postpartum. However, it is still difficult to prove the genotype-phenotype correlation, because many patients were compound heterozygotes (with two different mutations), lived in different environments at the time of diagnosis, and/or had several treatment regimes or various knowledge of the disease. (C) 2003 Wiley-Liss, Inc.