The biochemical and molecular spectrum of ornithine transcarbamylase deficiency
The biochemical and molecular spectrum of ornithine transcarbamylase deficiency
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DOI：
10.1023/a:1005353407220
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发表时间：
1998-06-01
影响因子：
4.2
通讯作者：
Allewell, NM
中科院分区：
文献类型：
--
作者：
Tuchman, M;Morizono, H;Allewell, NM
鸟氨酸转氨酶(OTCase)缺乏症是最常见的遗传性尿素循环障碍，是一种X连锁遗传性状。受影响的男性和杂合子女性的临床表型显示出从新生儿高氨性昏迷到无症状成年人的一系列严重程度。鸟氨酸转氨基甲酸酶是一个三聚体，每个全酶分子有三个活性部位，每个活性部位由一个多肽的结构域间区域和相邻多肽的一个极性域组成。OTC基因位于X染色体的短臂上，两个等位基因中的一个在女性细胞中失活。在受OTCase缺乏症影响的家庭中发现了大约140个突变，其中大多数都有他们自己的‘私人’突变。约7%的患者出现一个或多个外显子的大缺失，约9%的患者出现小的缺失或插入，其余的突变为单碱基替换。大约15%的突变会影响RNA剪接位点。重复突变在CpG二核苷酸热点中平均分布。通常情况下，导致新生儿疾病的突变会影响酶内部的氨基酸残基，特别是活性部位周围的氨基酸残基，而与起病较晚和较温和的表型相关的氨基酸残基往往位于蛋白质的表面。在前导肽的序列中发现的突变很少，比例上比成熟酶的序列少得多。只有少数突变在细菌或哺乳动物细胞中表达，用于研究它们的有害机制。表达突变的例子包括与迟发性疾病相关的R277W和R277Q，它们显著增加了鸟氨酸的K-m，使最适pH向更碱性方向移动，并降低了纯化的突变酶的热稳定性。R141Q(新生儿疾病)破坏了活性部位，而纯化的R40H突变体具有正常的催化功能，该突变可能会影响翻译后处理，如线粒体靶向。似乎大多数新的突变发生在男性精子中，然后传递给传播杂合子的女性。罕见的是，轻微的突变由无症状的男性传播给他们的女儿，随后导致后代男性的临床疾病。这些突变表达能力不同的原因目前尚不清楚，但很可能涉及环境和遗传修饰因素的组合。
Ornithine transcarbamylase (OTCase) deficiency, the most common inherited urea cycle disorder, is transmitted as an X-linked trait. The clinical phenotype in affected males as well as heterozygous females shows a spectrum of severity ranging from neonatal hyperammonaemic coma to asymptomatic adults. The ornithine transcarbamylase enzyme is a trimer with three active sites per holoenzyme molecule, each of which is composed of an interdomain region of one polypeptide and a polar domain of the adjacent polypeptide. The OTC gene is located on the short arm of the X-chromosome and one of the two alleles undergoes inactivation In female cells. Approximately 140 mutations have been found in families affected with OTCase deficiency, most having their own 'private' mutation. Large deletions of one exon or more are seen in approximately 7% of patients, small deletions or insertions are seen in about 9%, and the remaining mutations are single base substitutions. Approximately 15% of mutations affect RNA splicing sites. The recurrent mutations are distributed equally among CPG dinucleotide hot spots. Generally, mutations causing neonatal disease affect amino acid residues that are 'buried' in the interior of the enzyme, especially around the active site, while those associated with late onset and milder phenotypes tend to be located on the surface of the protein. Very few mutations have been found in the sequence of the leader peptide, proportionally much fewer than in the sequence of the mature enzyme. Only few of the mutations have been expressed in bacteria or mammalian cells for the study of their deleterious mechanisms. Examples of expressed mutations include R277W and R277Q associated with late-onset disease, which markedly increase the K-m for ornithine, shift the pH optimum to more alkaline and decrease the thermal stability of the purified mutant enzyme. R141Q (neonatal disease) disrupts the active site, whereas the purified R40H mutant has normal catalytic function and this mutation is likely to affect posttranslational processing such as mitochondrial targeting. It appears that most new mutations occur in male sperm and are then passed on to a transmitting heterozygous female. Uncommonly, mild mutations are transmitted by asymptomatic males to their daughters, subsequently resulting in clinical disease of males in future generations. The causes for variable expressivity of these mutations are currently unknown but are likely to involve a combination of environmental and genetic modifiers.