Update of the Mutation Spectrum and Clinical Correlations of over 360 Mutations in Eight Genes that Underlie the Neuronal Ceroid Lipofuscinoses
Update of the Mutation Spectrum and Clinical Correlations of over 360 Mutations in Eight Genes that Underlie the Neuronal Ceroid Lipofuscinoses
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DOI：
10.1002/humu.21624
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发表时间：
2012-01-01
期刊：
影响因子：
3.9
通讯作者：
Mole, Sara E.
中科院分区：
文献类型：
--
作者：
Kousi, Maria;Lehesjoki, Anna-Elina;Mole, Sara E.
神经性蜡样脂褐变（NCLs）是临床和遗传异质性的神经退行性疾病。大多数是常染色体隐性遗传。临床特征包括发病年龄可变、运动和智力下降、癫痫、视力丧失和过早死亡。已鉴定出8个基因（PPT1/CLN1、TPP1/CLN2、CLN3、CLN5、CLN6、MFSD8/CLN7、CLN8）的突变，预计还会存在更多的突变，包括两个暂时命名为CLN4和CLN9的基因。尽管有大量的体外和体内研究，但NCL蛋白的确切功能和疾病机制仍然难以捉摸。迄今为止，已知365种ncl致病突变，报告了91种新的致病突变。这些审查，重点是他们的复杂的相关表型。NCL谱中不同的突变可引起不同的疾病严重程度。NCLs是表型趋同或模仿和表型分化的例证。例如，CLN5、CLN6、MFSD8或CLN8的突变可能是临床上类似的晚期婴儿变异型NCL疾病的基础。不同的CLN8突变导致两种截然不同的疾病，轻度的CLN8疾病，EPMR（进行性癫痫伴智力迟钝），以及更严重的CLN8疾病，晚期婴儿变异，就是表型差异的例证。对ncl的遗传理解的增加导致了诊断方法的改进，并且最近提出了一个新的命名法。[j], 2012。(C) 2011 Wiley期刊公司
The neuronal ceroid lipofuscinoses (NCLs) are clinically and genetically heterogeneous neurodegenerative disorders. Most are autosomal recessively inherited. Clinical features include a variable age of onset, motor and mental decline, epilepsy, visual loss, and premature death. Mutations in eight genes (PPT1/CLN1, TPP1/CLN2, CLN3, CLN5, CLN6, MFSD8/CLN7, CLN8) have been identified and several more are predicted to exist, including two provisionally named CLN4 and CLN9. Despite excessive in vitro and in vivo studies, the precise functions of the NCL proteins and the disease mechanisms remain elusive. To date 365 NCL-causing mutations are known, with 91 novel disease-causing mutations reported. These are reviewed with an emphasis on their complex correlation to phenotypes. Different mutations within the NCL spectrum can cause variable disease severity. The NCLs exemplify both phenotypic convergence or mimicry and phenotypic divergence. For example, mutations in CLN5, CLN6, MFSD8, or CLN8 can underlie the clinically similar late infantile variant NCL disease. Phenotypic divergence is exemplified by different CLN8 mutations giving rise to two very different diseases, the mild CLN8 disease, EPMR (progressive epilepsy with mental retardation), and the more severe CLN8 disease, late infantile variant. The increase in the genetic understanding of the NCLs has led to improved diagnostic approaches, and the recent proposal of a new nomenclature. Hum Mutat 33:42-63, 2012. (C) 2011 Wiley Periodicals, Inc.