Genotype-phenotype correlations for EPM2A mutations in Lafora's progressive myoclonus epilepsy:: exon 1 mutations associate with an early-onset cognitive deficit subphenotype
Genotype-phenotype correlations for EPM2A mutations in Lafora's progressive myoclonus epilepsy:: exon 1 mutations associate with an early-onset cognitive deficit subphenotype
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DOI：
10.1093/hmg/11.11.1263
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发表时间：
2002-05-15
影响因子：
3.5
通讯作者：
Yamakawa, K
中科院分区：
文献类型：
--
作者：
Ganesh, S;Delgado-Escueta, A;Yamakawa, K
编码双特异性磷酸酶（laforin）的EPM 2A基因突变导致一种常染色体隐性遗传的致命疾病，称为Lafora病（LD），经典描述为一种突发性刺激敏感性肌阵挛、癫痫和神经功能恶化。在此，我们将EPM 2A突变与22例患者的表型相关联对14个家系进行分析，确定了两个亚综合征：（1）典型LD，伴有突然发作的刺激敏感性大发作、失神和肌阵挛性癫痫发作，随后出现痴呆和神经功能恶化，主要与外显子4突变相关（ii）非典型LD伴儿童期发作的阅读障碍和学习障碍，随后为癫痫和神经功能恶化，主要与外显子1突变相关（P=0.0015）。为了更好地理解这两个亚综合征，我们研究了碳水化合物结合结构域（CBD-4;由外显子1编码）中的五个错义突变和双重磷酸酶结构域（DSPD;由外显子3和4编码）中的三个错义突变对HeLa细胞中laforin细胞内定位的影响。三个突变蛋白（T1941，G279 S和Y294 N）在DSPD中的表达形成了泛素阳性的胞质聚集体，表明它们是为降解而设置的折叠突变体。相比之下，三个CBD-4突变体均未显示细胞质凝集。然而，CBD-4突变体W32 G和R108 C靶向细胞质和细胞核，表明laforin降低了其对多聚核糖体的通常亲和力。因此，我们的数据代表了LD的一种新的儿童综合征的第一份报告。我们的结果还为laforin的CBD-4和DSP结构域在LD两个亚综合征的病因中的不同作用提供了线索。
Mutations in the EPM2A gene encoding a dual-specificity phosphatase (laforin) cause an autosomal recessive fatal disorder called Lafora's disease (LD) classically described as an adolescent-onset stimulus-sensitive myoclonus, epilepsy and neurologic deterioration. Here we related mutations in EPM2A with phenotypes of 22 patients (14 families) and identified two subsyndromes: (I) classical LD with adolescent-onset stimulus-sensitive grand mal, absence and myoclonic seizures followed by dementia and neurologic deterioration, and associated mainly with mutations in exon 4 (P=0.0007); (ii) atypical LD with childhood-onset dyslexia and learning disorder followed by epilepsy and neurologic deterioration, and associated mainly with mutations in exon 1 (P=0.0015). To understand the two subsyndromes better, we investigated the effect of five missense mutations in the carbohydrate-binding domain (CBD-4; coded by exon 1) and three missense mutations in the dual phosphatase domain (DSPD; coded by exons 3 and 4) on laforin's intracellular localization in HeLa cells. Expression of three mutant proteins (T1941, G279S and Y294N) in DSPD formed ubiquitin-positive cytoplasmic aggregates, suggesting that they were folding mutants set for degradation. In contrast, none of the three CBD-4 mutants showed cytoplasmic clumping. However, CBD-4 mutants W32G and R108C targeted both cytoplasm and nucleus, suggesting that laforin had diminished its usual affinity for polysomes. Our data, thus, represent the first report of a novel childhood syndrome for LD. Our results also provide clues for distinct roles for the CBD-4 and DSP domains of laforin in the etiology of two subsyndromes of LD.