Transcript and in silico analysis of CLN3 in juvenile neuronal ceroid lipofuscinosis and associated mouse models
Transcript and in silico analysis of CLN3 in juvenile neuronal ceroid lipofuscinosis and associated mouse models
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DOI：
10.1093/hmg/ddn228
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发表时间：
2008-11-01
影响因子：
3.5
通讯作者：
Pearce, David A.
中科院分区：
文献类型：
--
作者：
Chan, Chun-Hung;Mitchison, Hannah M.;Pearce, David A.
青少年神经元蜡样脂褐质沉积症（JNCL），通常被称为Batten病，是一种以失明、癫痫发作、运动和认知下降为特征的儿童进行性神经退行性疾病，导致成年早期死亡。CLN 3基因（编码一种功能未知的推定溶酶体蛋白）内的突变是JNCL的根本原因。超过85%的JNCL患者具有Ikb缺失，其被预测为导致截短的CLN 3蛋白，并且被推测为无效突变。Kitzmuller等人（1）最近的一项研究表明，1 kb缺失相关的截短蛋白可能具有部分功能，并提出JNCL是一种突变特异性疾病。此外，最初和最广泛使用的JNCL小鼠模型Cln 3（Delta ex 1 -6）小鼠作为真正的无效突变体的有效性受到质疑。我们报告了在1 kb缺失患者的细胞中，截短的CLN 3基因产物的转录水平大幅下降。我们认为截短的CLN 3蛋白不太可能在JNCL患者中表达，因为RNA和蛋白质水平的细胞质量控制机制可能会降解突变体转录物和多肽。此外，我们目前的分析确定表达的转录本存在于Cln 3（三角洲ex 1 -6）小鼠大脑。从表达的Cln 3（Delta ex 1 -6）小鼠转录本的分析，结合计算机预测的预期后果的Cln 3（Delta ex 1 -6）突变对这些转录本，我们认为，异常的Cln 3蛋白不太可能在这种疾病模型中表达。总之，我们的结果表明，与JNCL相关的最常见的突变导致功能性CLN 3的丧失，Cln 3（Delta ex 1 -6）小鼠携带无效Cln 3等位基因，因此它代表了这种疾病的有效模型。
Juvenile neuronal ceroid lipofuscinoses ( JNCL), commonly known as Batten disease, is a progressive neurodegenerative disorder of childhood characterized by blindness, seizures, motor and cognitive decline, leading to death in early adulthood. Mutations within the CLN3 gene, which encodes a putative lysosomal protein of unknown function, are the underlying cause of JNCL. Over 85% of JNCL patients harbor a 1 kb deletion that is predicted to result in a truncated CLN3 protein and is presumed to be a null mutation. A recent study by Kitzmuller et al. ( 1) suggested that the 1 kb deletion- associated truncated protein may have partial function, and proposed that JNCL is a mutation- specific disease. In addition, the validity of the original and most widely utilized JNCL mouse model, the Cln3(Delta ex1-6) mouse, as a true null mutant was questioned. We report a substantial decrease in the transcript level of the truncated CLN3 gene product in cells from 1 kb deletion patients. We contend that the truncated CLN3 protein is unlikely to be expressed in JNCL patients since cellular quality control mechanisms at the RNA and protein levels are likely to degrade the mutant transcript and polypeptides. Moreover, we present analysis identifying the expressed transcripts present in Cln3(Delta ex1-6) mouse brain. From the analysis of expressed Cln3(Delta ex1-6) mouse transcripts, combined with in silico prediction of the expected consequences of the Cln3(Delta ex1-6) mutation on these transcripts, we argue that aberrant Cln3 proteins are unlikely to be expressed in this disease model. Taken together our results indicate that the most common mutation associated with JNCL results in a loss of functional CLN3, that the Cln3(Delta ex1-6) mouse harbors a null Cln3 allele, and that it therefore represents a valid model for this disease.