Mutational spectrum of the EPM2A gene in progressive myoclonus epilepsy of Lafora:: high degree of allelic heterogeneity and prevalence of deletions
Mutational spectrum of the EPM2A gene in progressive myoclonus epilepsy of Lafora:: high degree of allelic heterogeneity and prevalence of deletions
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DOI：
10.1038/sj.ejhg.5200571
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发表时间：
2000-12-01
影响因子：
5.2
通讯作者：
Serratosa, JM
中科院分区：
文献类型：
--
作者：
Gómez-Garre, P;Sanz, Y;Serratosa, JM
Lafora型进行性肌阵挛癫痫(Lafora病)是一种常染色体隐性遗传病，以癫痫、肌阵挛、进行性神经恶化和细胞内存在糖原样包涵体(Lafora小体)为特征。我们最近克隆了拉福拉病的主要基因(EPM2A)，并对相应的产物进行了鉴定，推测是一种蛋白酪氨酸磷酸酶(LAFPTPase)。本文报道了68条拉福拉病染色体上EPM2A基因的完整编码序列及其序列分析。我们描述了11个新的突变：3个错义突变(F84L、G240S和P301L)，1个无义突变(Y86Stop)，3个<；40bp微缺失(K90f，EX1-32bpdel，EX1-33bpdel)，以及两个影响整个外显子1的缺失(EX1-del1和EX1-del2)。此外，我们还发现3例患者在非外显子微卫星EPM2A-3或EPM2A-4上存在零等位基因，提示存在影响外显子2的两个截然不同的>；3kb缺失(ex2-del1和ex2-del2)。考虑到这些突变，到目前为止，在EPM2A基因中总共描述了25个突变，其中60%产生截断。尽管存在这种显著的等位基因异质性，但在大约40%的拉福拉病患者中发现了R241停止EPM2A突变。我们还报道了EPM2A基因中5个新的微卫星标记和1个SNP的特征，并描述了正常和EPM2A染色体上这些位点上等位基因的单倍型关联。这一分析表明，创始人效应和复发都是西班牙R241 Stop突变相对较高的原因之一。这里报道的数据首次系统分析了拉福拉病患者EPM2A基因的突变事件，并为了解不同EPM2A等位基因的起源和进化提供了洞察力。
Progressive myoclonus epilepsy of the Lafora type (Lafora disease) is an autosomal recessive disease characterised by epilepsy, myoclonus, progressive neurological deterioration and the presence of glycogen-like intracellular inclusion bodies (Lafora bodies). We recently cloned the major gene for Lafora disease (EPM2A) and characterised the corresponding product, a putative protein tyrosine phosphatase (LAFPTPase). Here we report the complete coding sequence of the EPM2A gene and the analysis of this gene in 68 Lafora disease chromosomes. We describe 11 novel mutations: three missense (F84L, G240S and P301L), one nonsense (Y86stop), three < 40 bp microdeletions (K90fs, Ex1-32bpdel, Ex1-33bpdel), and two deletions affecting the entire exon 1 (Ex1-del1 and Ex1-del2). In addition, we have identified three patients with a null allele in non-exonic microsatellites EPM2A-3 or EPM2A-4, suggesting the presence of two distinct > 3 kb deletions affecting exon 2 (Ex2-del1 and Ex2-del2). Considering these mutations, a total of 25 mutations, 60% of them generating truncations, have been described thus far in the EPM2A gene. In spite of this remarkable allelic heterogeneity, the R241stop EPM2A mutation was found in approximately 40% of the Lafora disease patients. We also report the characterisation of five new microsatellite markers and one SNP in the EPM2A gene and describe the haplotypic associations of alleles at these sites in normal and EPM2A chromosomes. This analysis suggests that both founder effect and recurrence have contributed to the relatively high prevalence of R241stop mutation in Spain. The data reported here represent the first systematic analysis of the mutational events in the EPM2A gene in Lafora disease patients and provide insight into the origin and evolution of the different EPM2A alleles.