Mutations and Polymorphisms in the Human Argininosuccinate Lyase (ASL) Gene
Mutations and Polymorphisms in the Human Argininosuccinate Lyase (ASL) Gene
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DOI：
10.1002/humu.22469
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发表时间：
2014-01-01
期刊：
影响因子：
3.9
通讯作者：
Haeberle, Johannes
中科院分区：
文献类型：
--
作者：
Balmer, Cecile;Pandey, Amit V.;Haeberle, Johannes
精氨酸琥珀酸裂解酶缺乏症（ASLD）是由精氨酸琥珀酸裂解酶（ASL）基因编码的尿素循环酶缺陷引起的。患者通常在出生后早期出现高氨血症，但也可在新生儿期以外出现，主要由过度的蛋白质分解代谢引起。临床病程包括仅在尿液中排泄生化标志物精氨酸琥珀酸的无症状个体，以及首次出现高氨失代偿的患者。一些没有高氨血症的病人会发展成严重的神经系统疾病。在这里，我们通过收集所有已发表的（n=67）以及ASL基因的新突变（n=67）提供ASLD分子基础的更新。我们收集了223例ASLD患者中所有160种不同基因型的数据，包括临床病程。最后，我们提出了结构上的考虑，重点关注突变与ASL同四聚体形成的相关性。ASLD可以被认为是一种泛民族疾病，仅在芬兰人（C . 299t >C, p.Ile100Thr）和阿拉伯人（C . 1060c >T, p.Gln354*）人群中发现单一始祖突变。大多数突变是私人的，只有少数基因型在不相关的患者中复发。大多数突变是错义突变，包括一些更频繁发生的突变，如p.a g12gln、p.a ile100thr、p.a val178met、p.a g186trp、p.a gl189gly、p.a gln286arg和p.a g385cys。
Argininosuccinate lyase deficiency (ASLD) is caused by a defect of the urea cycle enzyme argininosuccinate lyase (ASL) encoded by the ASL gene. Patients often present early after birth with hyperammonemia but can also manifest outside the neonatal period mainly triggered by excessive protein catabolism. Clinical courses comprise asymptomatic individuals who only excrete the biochemical marker, argininosuccinic acid, in urine, and patients who succumb to their first hyperammonemic decompensation. Some patients without any hyperammonemia develop severe neurological disease. Here, we are providing an update on the molecular basis of ASLD by collecting all published (n=67) as well as novel mutations (n=67) of the ASL gene. We compile data on all 160 different genotypes ever identified in 223 ASLD patients, including clinical courses whenever available. Finally, we are presenting structural considerations focusing on the relevance of mutations for ASL homotetramer formation. ASLD can be considered as a panethnic disease with only single founder mutations identified in the Finnish (c.299T>C, p.Ile100Thr) and Arab (c.1060C>T, p.Gln354*) population. Most mutations are private with only few genotypes recurring in unrelated patients. The majority of mutations are missense changes including some with more frequent occurrence such as p.Arg12Gln, p.Ile100Thr, p.Val178Met, p.Arg186Trp, p.Glu189Gly, p.Gln286Arg, and p.Arg385Cys.