Lafora's Progressive Myoclonus Epilepsy

拉福拉进行性肌阵挛癫痫

• 批准号: 6529980
• 负责人: ANTONIO V. DELGADO-ESCUETA
• 金额: $ 22.05万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-24 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6529980
• 关键词: adolescence (12-20); adult human (21+); ataxia; child (0-11); clinical research; disease /disorder model; enzyme activity; gene expression; gene mutation; gene targeting; genetically modified animals; genotype; human subject; immunocytochemistry; in situ hybridization; inclusion body; laboratory mouse; learning disorders; memory disorders; myoclonus epilepsy; neural degeneration; neurogenetics; pathologic process; phenotype; protein tyrosine phosphatase; yeast two hybrid system

Lafora's PME is an autosomal recessive fatal disorder characterized by childhood learning disorder or adolescent stimuli sensitive myoclonic seizures, ataxia and progressive neurologic deterioration. In 1995 we mapped the Lafora gene locus in chromosome 6q24. In 1998 we reported mutations in a novel gene (EPM2A) that encodes a protein (laforin) and, in 2000, proved that laforin is actually a dual specificity protein tyrosine phosphatase (ds-PTP), 38 kDa in size and cytoplasmic in location, associated with polyribosomes. Phenotype-genotype correlations and intracellular targeting with two natural mutants in exon 3 or exon 4 found in adolescent onset epilepsy resulted in ubiquitin positive perinuclear aggregates. Intracellular targeting of natural mutants in exon l, found in childhood learning disorders, did not produce the same results. These results suggest that laforin is involved in translational regulation and that protein misfolding and degradation produce adolescent epilepsy phenotypes caused by missense mutations in exon 3 and 4. How missense mutations in exon 1 produce childhood learning disorder need to be explored further. Now we propose to: (l) Continue phenotype-genotype correlations by (a) contrasting mutations in childhood onset learning disorder against adolescent onset epilepsy in new lafora patients; (b) completing sequence of Laforin promotor regions and comparing transcripts of exon 1 versus exons 2, 3 and 4, (c) analyzing intracellular targeting of missense mutations in exon 1 versus exon 3 and 4, (d) producing homozygous null mutants of exon 1 KO mice models and contrasting their phenotypes with homozygous null mutants of exon 4 KO mice models. (2) Use immunocytochemistry and in situ hybridization for studies of development and functions of Laforin in brains of normal mice and humans and mice and humans with Lafora's PME. (3) Search for the second gene (EPM2B) for Lafora's PME. These advances raise our hopes for developing treatment(s) for this fatal epilepsy.

Lafora的PME是一种常染色体隐性致命疾病，其特征是儿童学习障碍或青少年刺激敏感的肌阵挛性癫痫发作，共济失调和进行性神经系统恶化。 1995年，我们在6q24染色体中绘制了Lafora基因基因座。 在1998年，我们报道了编码蛋白质（Laforin）的新基因（EPM2A）中的突变，并在2000年证明了Laforin实际上是一种双重特异性蛋白酪氨酸磷酸酶（DS-PTP），大小为38 kDa的位置和细胞质的位置，与多幼型相关。 在青少年发作癫痫中发现的外显子3或外显子4中两个天然突变体的表型基因型相关性和细胞内靶向导致泛素阳性核周聚集体。 在儿童学习障碍中发现的外显子L中天然突变体的细胞内靶向并未产生相同的结果。 这些结果表明，拉福林参与了翻译调节，蛋白质的错误折叠和降解会产生由外显子3和4中的错义突变引起的青春期癫痫表型。外显子1中的错义突变如何产生童年学习障碍需要进一步探索儿童学习障碍。 现在，我们建议：（l）通过（a）在新拉福拉患者中对青少年开始癫痫的儿童发作学习障碍的对比突变来继续表型基因型相关性； (b) completing sequence of Laforin promotor regions and comparing transcripts of exon 1 versus exons 2, 3 and 4, (c) analyzing intracellular targeting of missense mutations in exon 1 versus exon 3 and 4, (d) producing homozygous null mutants of exon 1 KO mice models and contrasting their phenotypes with homozygous null mutants of exon 4 KO mice models. （2）使用免疫细胞化学和原位杂交来研究Laforin在正常小鼠，人类以及小鼠和人类与Lafora的PME的大脑中的发育和功能研究。 （3）在Lafora的PME中搜索第二个基因（EPM2B）。 这些进步提高了我们对这种致命癫痫的治疗的希望。