Tuchman M, Morizono H, Rajagopal B S, Plante R J, Allewell N M
Department of Pediatrics, Medical School, University of Minnesota, St. Paul, USA.
J Inherit Metab Dis. 1998;21 Suppl 1:40-58. doi: 10.1023/a:1005353407220.
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 Km 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.
鸟氨酸转氨甲酰酶（OTCase）缺乏症是最常见的遗传性尿素循环障碍，呈X连锁遗传。受影响的男性以及杂合子女性的临床表型严重程度不一，从新生儿高氨血症昏迷到无症状的成年人都有。鸟氨酸转氨甲酰酶是一种三聚体，每个全酶分子有三个活性位点，每个活性位点由一个多肽的结构域间区域和相邻多肽的极性结构域组成。OTC基因位于X染色体短臂上，在女性细胞中两个等位基因中的一个会发生失活。在受OTCase缺乏症影响的家族中已发现约140种突变，大多数有其自身的“私人”突变。约7%的患者可见一个或多个外显子的大片段缺失，约9%可见小缺失或插入，其余突变是单碱基替换。约15%的突变影响RNA剪接位点。反复出现的突变在CpG二核苷酸热点中均匀分布。一般来说，导致新生儿疾病的突变影响“埋藏”在酶内部的氨基酸残基，尤其是活性位点周围，而与迟发性和较轻表型相关的突变往往位于蛋白质表面。在前导肽序列中发现的突变很少，按比例比成熟酶序列中的少得多。只有少数突变已在细菌或哺乳动物细胞中表达以研究其有害机制。已表达突变的例子包括与迟发性疾病相关的R277W和R277Q，它们显著增加鸟氨酸的Km值，将最适pH值移向更碱性并降低纯化突变酶的热稳定性。R141Q（新生儿疾病）破坏活性位点，而纯化的R40H突变体具有正常的催化功能，这种突变可能影响翻译后加工，如线粒体靶向。似乎大多数新突变发生在男性精子中，然后传递给传递性杂合子女性。罕见的情况是，轻度突变由无症状男性传递给其女儿，随后导致后代男性出现临床疾病。这些突变可变表达的原因目前尚不清楚，但可能涉及环境和遗传修饰因子的组合。
