An XPA gene splicing mutation resulting in trace protein expression in an elderly xeroderma pigmentosum group A patient without neurological abnormalities.
An XPA gene splicing mutation resulting in trace protein expression in an elderly xeroderma pigmentosum group A patient without neurological abnormalities.
复制标题
XPA 基因剪接突变导致无神经系统异常的老年着色性干皮病 A 组患者中微量蛋白表达。
DOI：
10.1111/bjd.15051
复制
发表时间：
2017
影响因子：
10.3
通讯作者：
Moriwaki S.
中科院分区：
文献类型：
--
作者：
Takahashi Y;Endo Y;Kusaka A;Nakamaura S;Nakazawa Y;Ogi T;Uryu M;Tsuji M;Furue M;Moriwaki S.
在A组着色性干皮病（XP-A）患者中观察到XPA基因突变与症状严重程度之间存在一定的关系。在DNA结合结构域内发生突变的患者通常表现出严重的症状，而在同一结构域中发生剪接突变有时会导致非常轻微的症状。这种不一致性可以通过从正常剪接的转录物产生的少量功能性XPA蛋白来解释。我们在此报告的情况下，成人日本患者XP‐A异常轻微的症状。我们在XPA基因的外显子4中发现了一个纯合的c.529G>A突变，该突变导致外显子4中29 bp缺失的异常剪接，导致移码。可观察到完整的mRNA，但Western印迹分析未能检测到任何正常的XPA蛋白。因此，我们评估了正常细胞中的DNA修复能力，其中XPA表达被人为地减少。修复能力仍然存在于具有微量XPA蛋白的细胞中。相比之下，来自我们的轻度症状患者的细胞的修复能力较差，但与来自具有严重症状的XP-A患者的细胞相比仍然显着。这些结果提供了强有力的证据，表明痕量水平的XPA蛋白仍然可以发挥相对较强的修复能力，仅导致轻度表型。
A certain relationship betweenXPAgene mutations and the severity of symptoms has been observed in patients with xeroderma pigmentosum group A (XP‐A). Patients with mutations within the DNA‐binding domain usually exhibit severe symptoms, whereas splicing mutations in the same domain sometimes cause very mild symptoms. This inconsistency can be explained by a small amount of functional XPA protein produced from normally spliced transcripts. We herein report the case of an adult Japanese patient with XP‐A with unusually mild symptoms. We identified a homozygous c.529G>A mutation in exon 4 of theXPAgene, which resulted in aberrant splicing with a 29‐bp deletion in exon 4 causing a frameshift. Intact mRNA was observable, but a Western blot analysis failed to detect any normal XPA protein. We therefore evaluated the DNA repair capacity in normal cells in which the XPA expression was artificially diminished. The repair capacity was still present in cells with trace levels of the XPA protein. The repair capacity of the cells derived from our patient with mild symptoms was poor by comparison, but still significant compared with that of the cells derived from a patient with XP‐A with severe symptoms. These results provide strong evidence that a trace level of XPA protein can still exert a relatively strong repair capacity, resulting in only a mild phenotype.