SON-Related Zhu-Tokita-Takenouchi-Kim Syndrome With Recurrent Hemiplegic Migraine: Putative Role of PRRT2.
SON-Related Zhu-Tokita-Takenouchi-Kim Syndrome With Recurrent Hemiplegic Migraine: Putative Role of PRRT2.
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DOI：
10.1212/nxg.0000000000200062
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发表时间：
2023-06
影响因子：
3.1
通讯作者：
Ahn, Eun-Young Erin
中科院分区：
文献类型：
--
作者：
Langford, Jordan;Vukadin, Lana;Carey, John C.;Botto, Lorenzo D.;Velinder, Matt;Mao, Rong;Miller, Christine E.;Filloux, Francis;Ahn, Eun-Young Erin
Zhu-Tokita-Takenouchi-Kim (ZTTK) 综合征 (OMIM 617140) 是一种最近发现的由 SON 杂合功能丧失 (LoF) 变异引起的神经发育障碍。由于 SON 蛋白起到 RNA 剪接调节因子的作用，因此研究表明 ZTTK 综合征的一些临床特征可归因于 RNA 剪接异常。在 ZTTK 综合征患者中观察到了多种神经系统特征，包括癫痫发作/癫痫和其他脑电图异常。然而，ZTTK 综合征中的 SON LoF 与偏瘫性偏头痛之间的关系仍不清楚。我们发现了一名 SON 致病性变异患者，其表现出 ZTTK 综合征的典型临床特征，并经历过偏瘫性偏头痛的反复发作。为了明确临床特征，对偏瘫性偏头痛发作期间和发作后的脑部 MRI 和 EEG 进行了表征。为了确定这种临床表现的分子机制，我们通过定量 RT-PCR 研究了小干扰 RNA (siRNA) 介导的 SON 敲低对已知与偏瘫性偏头痛相关的 CACNA1A、ATP1A2、SCN1A 和 PRRT2 基因 mRNA 表达的影响。使用针对特定外显子的引物通过 RT-PCR 进一步检查 PRRT2 对 SON 敲低的前 mRNA 剪接。本例患者的偏瘫性偏头痛通常在轻度闭合性头部损伤后反复发作，而在最严重的发作期间会出现反复癫痫发作。发作期间发现短暂的半球皮质间质水肿和不对称脑电图减慢。我们的 siRNA 实验表明，SON 敲低显着降低了 U87MG 和 SH-SY5Y 细胞系中 PRRT2 mRNA 水平，但没有观察到 CACNA1A、ATP1A2 和 SCN1A mRNA 表达的降低。我们进一步发现 SON 敲低导致内含子 2 从 PRRT2 前体 mRNA 中去除失败，导致过早终止密码子阻止功能完整的全长 PRRT2 的生成。该报告将复发性偏瘫性偏头痛确定为 ZTTK 综合征的一种新的临床表现，进一步表征了这一临床特征，并为 SON LoF 引起的 PRRT2 下调作为引起偏瘫性偏头痛的机制提供了证据。对于患有复发性偏瘫性偏头痛的个体，可能需要检查 SON 基因。
Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome (OMIM 617140) is a recently identified neurodevelopmental disorder caused by heterozygous loss-of-function (LoF) variants in SON. Because the SON protein functions as an RNA-splicing regulator, it has been shown that some clinical features of ZTTK syndrome can be attributed to abnormal RNA splicing. Several neurologic features have been observed in patients with ZTTK syndrome, including seizure/epilepsy and other EEG abnormalities. However, a relationship between SON LoF in ZTTK syndrome and hemiplegic migraine remains unknown. We identified a patient with a pathogenic variant in SON who shows typical clinical features of ZTTK syndrome and experienced recurrent episodes of hemiplegic migraine. To define clinical features, brain MRI and EEG during and after episodes of hemiplegic migraine were characterized. To identify molecular mechanisms for this clinical presentation, we investigated the impact of small interfering RNA (siRNA)-mediated SON knockdown on mRNA expression of the CACNA1A, ATP1A2, SCN1A, and PRRT2 genes, known to be associated with hemiplegic migraine, by quantitative RT-PCR. Pre-mRNA splicing of PRRT2 on SON knockdown was further examined by RT-PCR using primers targeting specific exons. Recurrent episodes of hemiplegic migraine in our patient typically followed modest closed head injuries, and recurrent seizures occurred during the most severe of these episodes. Transient hemispheric cortical interstitial edema and asymmetric EEG slowing were identified during episodes. Our siRNA experiments revealed that SON knockdown significantly reduces PRRT2 mRNA levels in U87MG and SH-SY5Y cell lines, although a reduction in CACNA1A, ATP1A2, and SCN1A mRNA expression was not observed. We further identified that SON knockdown leads to failure in intron 2 removal from PRRT2 pre-mRNA, resulting in a premature termination codon that blocks the generation of functionally intact full-length PRRT2. This report identifies recurrent hemiplegic migraine as a novel clinical manifestation of ZTTK syndrome, further characterizes this clinical feature, and provides evidence for downregulation of PRRT2 caused by SON LoF as a mechanism causing hemiplegic migraine. Examination of the SON gene may be indicated in individuals with recurrent hemiplegic migraine.
影响因子：
2.6
作者：
Luo HY;Xie LL;Hong SQ;Li XJ;Li M;Hu Y;Ma JN;Wu P;Zhong M;Cheng M;Li TS;Jiang L
通讯作者：
Jiang L
影响因子：
3.7
作者：
Lee YC;Lee MJ;Yu HY;Chen C;Hsu CH;Lin KP;Liao KK;Chang MH;Liao YC;Soong BW
通讯作者：
Soong BW