Fukao Toshiyuki, Sass Jörn Oliver, Kursula Petri, Thimm Eva, Wendel Udo, Ficicioglu Can, Monastiri Kamel, Guffon Nathalie, Barić Ivo, Zabot Marie-Therese, Kondo Naomi
Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Gifu 501-1194, Japan.
Biochim Biophys Acta. 2011 May;1812(5):619-24. doi: 10.1016/j.bbadis.2011.01.015. Epub 2011 Feb 2.
Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency is an inborn error of ketone body metabolism and causes episodic ketoacidosis. We report clinical and molecular analyses of 5 patients with SCOT deficiency. Patients GS07, GS13, and GS14 are homozygotes of S405P, L327P, and R468C, respectively. GS17 and GS18 are compound heterozygotes for S226N and A215V, and V404F and E273X, respectively. These mutations have not been reported previously. Missense mutations were further characterized by transient expression analysis of mutant cDNAs. Among 6 missense mutations, mutants L327P, R468C, and A215V retained some residual activities and their mutant proteins were detected in immunoblot analysis following expression at 37°C. They were more stable at 30°C than 37°C, indicating their temperature sensitive character. The R468C mutant is a distinct temperature sensitive mutant which retained 12% and 51% of wild-type residual activities at 37 and 30°C, respectively. The S226N mutant protein was detected but retained no residual activity. Effects of missense mutations were predicted from the tertiary structure of the SCOT molecule. Main effects of these mutations were destabilization of SCOT molecules, and some of them also affected catalytic activity. Among 5 patients, GS07 and GS18 had null mutations in both alleles and the other three patients retained some residual SCOT activities. All 5 developed a first severe ketoacidotic crisis with blood gas pH <7.1, and experienced multiple ketoacidotic decompensations (two of them had seven such episodes). In general, the outcome was good even following multiple ketoacidotic events. Permanent ketosis or ketonuria is considered a pathognomonic feature of SCOT deficiency. However, this condition depends not only on residual activity but also on environmental factors.
琥珀酰辅酶A：3-酮酸辅酶A转移酶（SCOT）缺乏症是一种酮体代谢的先天性缺陷，可导致发作性酮症酸中毒。我们报告了5例SCOT缺乏症患者的临床和分子分析情况。患者GS07、GS13和GS14分别是S405P、L327P和R468C的纯合子。GS17和GS18分别是S226N与A215V以及V404F与E273X的复合杂合子。这些突变此前尚未见报道。通过对突变cDNA进行瞬时表达分析，对错义突变进行了进一步表征。在6个错义突变中，突变体L327P、R468C和A215V保留了一些残余活性，并且在37°C表达后通过免疫印迹分析检测到了它们的突变蛋白。它们在30°C时比在37°C时更稳定，表明其具有温度敏感性。R468C突变体是一种独特的温度敏感突变体，在37°C和30°C时分别保留了野生型残余活性的12%和51%。检测到了S226N突变蛋白，但未保留残余活性。根据SCOT分子的三级结构预测了错义突变的影响。这些突变的主要影响是使SCOT分子不稳定，其中一些还影响催化活性。在5例患者中，GS07和GS18的两个等位基因均存在无效突变，其他三名患者保留了一些残余的SCOT活性。所有5例患者均首次发生严重的酮症酸中毒危机，血气pH <7.1，并经历了多次酮症酸中毒失代偿（其中2例有7次这样的发作）。一般来说，即使经历多次酮症酸中毒事件，预后也良好。永久性酮血症或酮尿症被认为是SCOT缺乏症的特征性表现。然而，这种情况不仅取决于残余活性，还取决于环境因素。
