Mutations of PTPN23 in developmental and epileptic encephalopathy
Mutations of PTPN23 in developmental and epileptic encephalopathy
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DOI：
10.1007/s00439-017-1850-3
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发表时间：
2017-11-01
期刊：
影响因子：
5.3
通讯作者：
Borck, Guntram
中科院分区：
文献类型：
--
作者：
Sowada, Nadine;Hashem, Mais Omar;Borck, Guntram
发育性和癫痫性脑病(DeE)是一组预后不良的异质性神经发育障碍。最近的发现极大地扩展了癫痫脑病和DeE中突变的基因谱系，通常是以从头开始的方式，但在许多患者中，这种疾病的分子特征仍然不明确。在这里，我们描述了PTPN23中可能存在有害双等位基因变异的患者中的一种新形式的DeE。其表型特征为早发性耐药癫痫、严重的全身性发育迟缓、小头畸形，有时还会过早死亡。PTPN23编码一种强脑表达的酪氨酸磷酸酶，其在小鼠体内的敲除是胚胎致死的。结构建模支持识别的等位基因的有害影响。我们的数据表明，PTPN23突变会在人类中导致一种罕见的严重形式的常染色体隐性死亡，这一发现需要证实。
Developmental and epileptic encephalopathies (DEE) are a heterogeneous group of neurodevelopmental disorders with poor prognosis. Recent discoveries have greatly expanded the repertoire of genes that are mutated in epileptic encephalopathies and DEE, often in a de novo fashion, but in many patients, the disease remains molecularly uncharacterized. Here, we describe a new form of DEE in patients with likely deleterious biallelic variants in PTPN23. The phenotype is characterized by early onset drug-resistant epilepsy, severe and global developmental delay, microcephaly, and sometimes premature death. PTPN23 encodes a tyrosine phosphatase with strong brain expression, and its knockout in mouse is embryonically lethal. Structural modeling supports a deleterious effect of the identified alleles. Our data suggest that PTPN23 mutations cause a rare severe form of autosomal-recessive DEE in humans, a finding that requires confirmation.