Oppliger Leibundgut E O, Liechti-Gallati S, Colombo J P, Wermuth B
Department of Clinical Chemistry, University of Berne, Inselspital, Switzerland.
Hum Genet. 1995 Feb;95(2):191-6. doi: 10.1007/BF00209400.
Ornithine transcarbamylase (OTC) deficiency, the most common inborn error of the urea cycle, shows an X-linked inheritance with frequent new mutations. Investigations of patients with OTC deficiency have indicated an overproportionate share of mutations at CpG dinucleotides. These statistics may, however, be biased because of the easy detection of CpG mutations by screening for TaqI and MspI restriction sites. In the present study, we investigated 30 patients, with diagnosed OTC deficiency, for new sites with an increased probability of mutation by complete DNA sequence analysis of all ten exons of the OTC gene. In six patients, two codons in exons 2 and 5, respectively, contained novel recurrent mutations, all of them affecting CpG dinucleotides. They included C to T and G to A transitions in codon 40, changing an arginine to cysteine and histidine, respectively, and a C to T transition in codon 178 causing the substitution of threonine by methionine. The first two mutations were characterized by a mild clinical course with high risk of sudden death in late childhood or early adulthood, whereas the third mutation showed a more severe phenotypic expression. In addition to these novel mutations, we identified four patients with the known R277W mutation, making it the most common point mutation of the OTC gene.
鸟氨酸转氨甲酰酶（OTC）缺乏症是尿素循环中最常见的先天性代谢缺陷，呈X连锁遗传，且常有新的突变。对OTC缺乏症患者的研究表明，CpG二核苷酸处的突变比例过高。然而，这些统计数据可能存在偏差，因为通过筛查TaqI和MspI限制性酶切位点可轻松检测到CpG突变。在本研究中，我们通过对OTC基因的全部10个外显子进行完整的DNA序列分析，对30例确诊为OTC缺乏症的患者进行了研究，以寻找突变概率增加的新位点。在6例患者中，外显子2和5中的两个密码子分别出现了新的复发性突变，所有这些突变均影响CpG二核苷酸。它们包括密码子40中的C到T和G到A的转换，分别将精氨酸变为半胱氨酸和组氨酸，以及密码子178中的C到T的转换，导致苏氨酸被甲硫氨酸取代。前两个突变的临床病程较轻，但在儿童晚期或成年早期有较高的猝死风险，而第三个突变表现出更严重的表型表达。除了这些新突变外，我们还鉴定出了四名携带已知R277W突变的患者，使其成为OTC基因最常见的点突变。
