The neuronal ceroid lipofuscinoses in human EPMR and mnd mutant mice are associated with mutations in CLN8
The neuronal ceroid lipofuscinoses in human EPMR and mnd mutant mice are associated with mutations in CLN8
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DOI：
10.1038/13868
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发表时间：
1999-10-01
期刊：
影响因子：
30.8
通讯作者：
Lehesjoki, AE
中科院分区：
文献类型：
--
作者：
Ranta, S;Zhang, YH;Lehesjoki, AE
神经元蜡样脂褐质沉积症（NCL）是一组遗传异质性的进行性神经退行性疾病，其特征为各种组织中自发荧光脂色素的蓄积（1）。进行性癫痫伴精神发育迟滞（Progressive epilepsy with mental retardation，EPMR，MIM 600143）是近年来发现的一种新的NCL亚型（CLN 8），它是一种常染色体隐性遗传疾病，以5 ~ 10年的全身性癫痫发作为特征，随后出现进行性精神发育迟滞（progressive mental retardation，3）。在这里，我们报告的位置克隆的一个新的基因，CLN 8，这是突变的EPMR。它编码一种假定的跨膜蛋白。EPMR患者的错义突变（70 C->G，R24 G）是纯合的，而在433例对照中未发现纯合性。我们还克隆了小鼠Cln 8序列。它与CLN 8具有82%的核苷酸同一性，是携带人类突变的密码子的保守性，并定位于与运动神经元变性小鼠mnd（一种天然存在的小鼠NCL）相同的区域（参考文献4）。在mnd/mnd小鼠中，我们鉴定了纯合的1-bp插入（267- 268 insC，密码子90），预测了移码和截短的蛋白质。我们的数据表明，在这些orthopathy基因突变的基础NCL表型在人类和小鼠，并代表了自然发生的动物模型的NCL的分子基础的第一个描述。
The neuronal ceroid lipofuscinoses (NCLs) are a genetically heterogeneous group of progressive neurodegenerative disorders characterized by the accumulation of autofluorescent lipopigment in various tissues(1). Progressive epilepsy with mental retardation (EPMR, MIM 600143) was recently recognized as a new NCL subtype(2) (CLN8), It is an autosomal recessive disorder characterized by onset of generalized seizures between 5 and 10 years, and subsequent progressive mental retardation(3). Here we report the positional cloning of a novel gene, CLN8, which is mutated in EPMR. It encodes a putative transmembrane protein. EPMR patients were homozygous for a missense mutation (70C-->G, R24G) that was not found in homozygosity in 433 controls. We also cloned the mouse Cln8 sequence. It displays 82% nucleotide identity with CLN8, conservation of the codon harbouring the human mutation and is localized to the same region as the motor neuron degeneration mouse, mnd, a naturally occurring mouse NCL (ref. 4). In mnd/mnd mice, we identified a homozygous 1-bp insertion (267-268insC, codon 90) predicting a frameshift and a truncated protein. Our data demonstrate that mutations in these orthologous genes underlie NCL phenotypes in human and mouse, and represent the first description of the molecular basis of a naturally occurring animal model for NCL.