Developmental epileptic encephalopathy with hypomyelination and brain atrophy associated with PTPN23 variants affecting the assembly of UsnRNPs
Developmental epileptic encephalopathy with hypomyelination and brain atrophy associated with PTPN23 variants affecting the assembly of UsnRNPs
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DOI：
10.1038/s41431-018-0179-2
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发表时间：
2018-10-01
影响因子：
5.2
通讯作者：
Ploski, Rafal
中科院分区：
文献类型：
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作者：
Smigiel, Robert;Landsberg, Gerd;Ploski, Rafal
PTPN 23编码在包括神经元在内的所有细胞中发现的普遍表达的非受体型、无催化活性的蛋白酪氨酸磷酸酶。最近，我们已经确定了PTPN 23在细胞筛选系统识别的新的调节器的生存运动神经元（SMN）功能的剪接因子（富含尿苷的小核核糖核蛋白，UsnRNP）的组装。基于三个家族，隐性PTPN 23变异体与人类疾病暂时相关，但没有功能研究。在这里，我们描述了一个儿童先证者严重发育迟缓，癫痫，皮质盲，髓鞘形成不足和脑萎缩的MRI。全外显子组测序和家族研究显示了两种新的PTPN 23变体，c.1902C>G（p.（Asn634Lys））和c.2974delC（p.（Leu 992 Tyrfs *168）），其处于复合杂合状态，计算机模拟预测其具有损害性。当研究患者的成纤维细胞时，我们发现SMN的类似表达，但在Cajal小体（CB）中显示SMN积聚的细胞显著减少。在超过50%的不相关对照细胞成纤维细胞以及来自仅携带c.2974delC的亲本的成纤维细胞中，SMN在CB中强烈积累（p.（Leu 992 Tyrfs *168））变体（预测引起功能丧失）。相比之下，只有22%的细胞在患者成纤维细胞中显示相应的SMN蓄积（p = 1.9-2.5 x 10（-7）），同时显示较高水平的核质SMN。此外，患者细胞中的剩余积累显示出比对照或杂合wt/c.2974delC更弱的SMN信号（p.（Leu 992 Tyrfs *168））成纤维细胞。我们的报告首次描述了隐性PTPN 23变异体的临床表型，并通过功能研究证实了致病性。
PTPN23 encodes a ubiquitously expressed non-receptor type, catalytically inactive protein-tyrosine phosphatase found in all cells including neurons. Recently, we have identified PTPN23 in a cellular screen for the systematic identification of novel regulators of survival motor neuron (SMN) function in the assembly of splicing factors (Uridine-rich small nuclear ribonucleoproteins, UsnRNPs). Based on three families, recessive PTPN23 variants have been associated with human disease tentatively, without functional studies. Here, we describe a pediatric proband with severe developmental delay, epilepsy, cortical blindness, hypomyelination and brain atrophy on MRI. Whole exome sequencing and family study showed two novel PTPN23 variants, c.1902C>G (p.(Asn634Lys)) and c.2974delC (p.(Leu992Tyrfs*168)), in compound heterozygous state, which are predicted in silico to be damaging. When studying patient's fibroblasts we found similar expression of SMN but a dramatic reduction of cells displaying SMN accumulation in Cajal bodies (CB). SMN strongly accumulated in CB in more than 50% of unrelated control cell fibroblasts as well as in fibroblasts from the parent carrying only the c.2974delC (p.(Leu992Tyrfs*168)) variant (predicted to cause loss-of-function). In contrast, only 22% of cells showed respective SMN accumulations in patient fibroblasts (p = 1.9-2.5 x 10(-7)) while showing a higher level of nucleoplasmic SMN. Furthermore, the remaining accumulations in patient cells displayed weaker SMN signals than control or heterozygous wt/c.2974delC (p.(Leu992Tyrfs*168)) fibroblasts. Our report provides the first description of the clinical phenotype of recessive PTPN23 variants with pathogenicity substantiated by a functional study.