Mutations in DNAJC5, Encoding Cysteine-String Protein Alpha, Cause Autosomal-Dominant Adult-Onset Neuronal Ceroid Lipofuscinosis
Mutations in DNAJC5, Encoding Cysteine-String Protein Alpha, Cause Autosomal-Dominant Adult-Onset Neuronal Ceroid Lipofuscinosis
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DOI：
10.1016/j.ajhg.2011.07.003
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发表时间：
2011-08-12
影响因子：
9.8
通讯作者：
Kmoch, Stanislav
中科院分区：
文献类型：
--
作者：
Noskova, Lenka;Stranecky, Viktor;Kmoch, Stanislav
常染色体显性遗传性成人型神经型蜡样脂褐素沉着症(ANCL)是以神经组织中自身荧光储存物质积聚和神经变性为特征的疾病，发病年龄在30岁或以上。这种疾病的遗传和分子基础多年来一直不为人知。我们对来自20个单纯性病例家系和/或个体的患者进行了连锁图谱、基因表达分析、外显子测序和候选基因测序；我们在5个个体中发现了编码半胱氨酸串蛋白α(CSPα)的DNAJC5中的两个致病突变之一，C.346_348delCTC和C.344T>；G。这些突变分别导致缺失的p.Leu116del和氨基酸交换的p.Leu115Arg，位于蛋白质的半胱氨酸串域内，并影响棕榈酰化依赖的分选和神经细胞中CSPα的量。由此导致的功能性CSPα的缺失可能同时导致在受影响的个体中观察到的突触前功能障碍和进行性神经变性，以及以特有的蜡样沉积的形式在神经元中错误折叠和抗蛋白水解性蛋白的溶酶体积累。我们的工作代表了对遗传异质性的ANCL组进行基因解剖的重要一步。这也证实了CSPα在人类中的神经保护作用，并证明了CSPα在神经性蜡样脂褐素沉着症和其他以神经元蛋白聚集为表现的神经退行性疾病中的详细研究的必要性。
Autosomal-dominant adult-onset neuronal ceroid lipofuscinosis (ANCL) is characterized by accumulation of autofluorescent storage material in neural tissues and neurodegeneration and has an age of onset in the third decade of life or later. The genetic and molecular basis of the disease has remained unknown for many years. We carried out linkage mapping, gene-expression analysis, exome sequencing, and candidate-gene sequencing in affected individuals from 20 families and/or individuals with simplex cases; we identified in five individuals one of two disease-causing mutations, c.346_348delCTC and c.344T>G, in DNAJC5 encoding cysteine-string protein alpha (CSP alpha). These mutations-causing a deletion, p.Leu116del, and an amino acid exchange, p.Leu115Arg, respectively-are located within the cysteine-string domain of the protein and affect both palmitoylation-dependent sorting and the amount of CSP alpha in neuronal cells. The resulting depletion of functional CSP alpha might cause in parallel the presynaptic dysfunction and the progressive neurodegeneration observed in affected individuals and lysosomal accumulation of misfolded and proteolysis-resistant proteins in the form of characteristic ceroid deposits in neurons. Our work represents an important step in the genetic dissection of a genetically heterogeneous group of ANCLs. It also confirms a neuroprotective role for CSP alpha in humans and demonstrates the need for detailed investigation of CSP alpha in the neuronal ceroid lipofuscinoses and other neurodegenerative diseases presenting with neuronal protein aggregation.