Analysis of Potential Biomarkers and Modifier Genes Affecting the Clinical Course of CLN3 Disease
Analysis of Potential Biomarkers and Modifier Genes Affecting the Clinical Course of CLN3 Disease
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DOI：
10.2119/molmed.2010.00241
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发表时间：
2011-11-01
影响因子：
5.7
通讯作者：
Schulz, Angela
中科院分区：
文献类型：
--
作者：
Lebrun, Anne-Helene;Moll-Khosrawi, Parisa;Schulz, Angela
CLN 3基因突变导致青少年神经元蜡样质脂褐质沉积症，这是一种以视力丧失、癫痫和精神病恶化为特征的儿科神经退行性疾病。尽管大多数CLN 3患者在CLN 3基因中携带相同的1-kb缺失，但他们的疾病表型可能是可变的。本研究的目的是（i）研究具有相同基因型的CLN 3患者的临床表型，（ii）鉴定在CLN 3疾病中失调的基因，无论临床病程如何，其可用作生物标志物，以及（iii）发现影响疾病进展速度的修饰基因。使用已建立的临床评分系统，将总共25名1-kb缺失纯合的CLN 3患者分为快速、平均或缓慢疾病进展组。在8名具有不同疾病进展的CLN 3患者和匹配的对照中进行全基因组表达谱分析。该研究显示CLN 3患者的表型变异性较高。在所有CLN 3患者中有五个基因失调，并呈现该疾病的候选生物标志物。其中，双特异性磷酸酶2（DUSP 2）也在急性CLN 3耗尽的细胞模型和CbCln 3（Delta ex 7/8）小脑前体细胞中得到验证。共有13个基因在快速疾病进展的患者中上调，在缓慢疾病进展的患者中下调;一个基因以相反的方式表现出失调。在这些潜在的修饰基因中，Ras家族的小GTP酶的鸟嘌呤核苷酸交换因子1（RAPGEF 1）和转录因子Spi-B（SPIB）在急性CLN 3耗尽的细胞模型中被验证。这些发现表明，不同信号通路的差异扰动可能会改变疾病的进展，并提供深入了解CLN 3疾病和神经变性中神经元功能障碍的分子改变。(C)2011 Feinstein医学研究所，www.feinsteininstitute.org在线地址：http://www.molmed.org doi：10.2119/molmed.2010.00241
Mutations in the CLN3 gene lead to juvenile neuronal ceroid lipofuscinosis, a pediatric neurodegenerative disorder characterized by visual loss, epilepsy and psychomotor deterioration, Although most CLN3 patients carry the same 1-kb deletion in the CLN3 gene, their disease phenotype can be variable. The aims of this study were to (i) study the clinical phenotype in CLN3 patients with identical genotype, (ii) identify genes that are dysregulated in CLN3 disease regardless of the clinical course that could be useful as biomarkers, and (iii) find modifier genes that affect the progression rate of the disease. A total of 25 CLN3 patients homozygous for the 1-kb deletion were classified into groups with rapid, average or slow disease progression using an established clinical scoring system. Genome-wide expression profiling was performed in eight CLN3 patients with different disease progression and matched controls. The study showed high phenotype variability in CLN3 patients. Five genes were dysregulated in all CLN3 patients and present candidate biomarkers of the disease. Of those, dual specificity phosphatase 2 (DUSP2) was also validated in acutely CLN3-depleted cell models and in CbCln3(Delta ex7/8) cerebellar precursor cells. A total of 13 genes were upregulated in patients with rapid disease progression and downregulated in patients with slow disease progression; one gene showed dysregulation in the opposite way. Among these potential modifier genes, guanine nucleotide exchange factor 1 for small GTPases of the Ras family (RAPGEF1) and transcription factor Spi-B (SPIB) were validated in an acutely CLN3-depleted cell model. These findings indicate that differential perturbations of distinct signaling pathways might alter disease progression and provide insight into the molecular alterations underlying neuronal dysfunction in CLN3 disease and neurodegeneration in general. (C) 2011 The Feinstein Institute for Medical Research, www.feinsteininstitute.org Online address: http://www.molmed.org doi: 10.2119/molmed.2010.00241