A Novel CLN8 Mutation in Late-Infantile-Onset Neuronal Ceroid Lipofuscinosis (LINCL) Reveals Aspects of CLN8 Neurobiological Function
A Novel CLN8 Mutation in Late-Infantile-Onset Neuronal Ceroid Lipofuscinosis (LINCL) Reveals Aspects of CLN8 Neurobiological Function
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DOI：
10.1002/humu.21012
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发表时间：
2009-07-01
期刊：
影响因子：
3.9
通讯作者：
Bassi, Maria T.
中科院分区：
文献类型：
--
作者：
Vantaggiato, Chiara;Redaelli, Francesca;Bassi, Maria T.
晚发型婴儿型神经元蜡样质脂褐质沉积症（LINCL）是常染色体隐性遗传神经元蜡样质脂褐质沉积症（NCL）中遗传异质性最大的一组，在CLN 1、CLN 2、CLN 5、CLN 6、CLN 7（MFSD 8）和CLN 8基因中发现致病突变。CLN 8中的纯合突变与两种不同的表型相关：进行性癫痫和精神发育迟滞（EPMR），首先在芬兰发现;以及土耳其和意大利患者亚组中描述的晚期婴儿NCL（v-LINCL）变体。CLN 8编码的蛋白质的功能目前尚不清楚。在这里，我们报告了一个意大利v，LINCL患者的8号染色体完全同二体性，导致纯合性的母系遗传的3-bp缺失CLN 8基因（c.180_182delGAA，p.Lys61del）。值得注意的是，单亲二体性（UPD）从未被描述与NCL相关。此外，我们提供了CLN 8的生物学作用的证据，其特征在于在不同的神经元细胞模型中表达天然蛋白质、携带此处鉴定的突变的蛋白质或先前描述的三种另外的错义突变。我们的研究结果，通过基因沉默方法验证，表明CLN 8在神经元分化过程中的细胞增殖和保护细胞免于死亡中发挥作用。Mutat 30：1104-1116，2009. (C)2009 Wiley-Liss，Inc.
The late-infantile-onset forms of neuronal ceroid lipofuscinosis (LINCL) are the most genetically heterogeneous group among the autosomal recessive neuronal ceroid lipofuscinoses (NCLs), with causative mutations found in CLN1, CLN2, CLN5, CLN6, CLN7 (MFSD8), and CLN8 genes. Homozygous mutations in CLN8 are associated with two distinct phenotypes: progressive epilepsy and mental retardation (EPMR), first identified in Finland; and a variant of late-infantile NCL (v-LINCL) described in a Subset of Turkish and Italian patients. The function of the protein encoded by CLN8 is currently unknown. Here we report the identification of an Italian v,LINCL patient with a complete isodisomy of chromosome 8, leading to homozygosity of a maternally-inherited 3-bp deletion in CLN8 gene (c.180_182delGAA, p.Lys61del). Notably, uniparental disomy (UPD) has never been described associated with the NCLs. In addition, we provide evidence of the biological role of CLN8 characterized by expressing in different neuronal cell models the native protein, the protein carrying the mutation identified here, or three additional missense mutations previously described. Our results, validated through a gene silencing approach, indicate that CLN8 plays a role in cell proliferation during neuronal differentiation and in protection against cell death. Hum Mutat 30:1104-1116, 2009. (C) 2009 Wiley-Liss, Inc.