Presynaptic congenital myasthenic syndrome with altered synaptic vesicle homeostasis linked to compound heterozygous sequence variants in RPH3A.
Presynaptic congenital myasthenic syndrome with altered synaptic vesicle homeostasis linked to compound heterozygous sequence variants in RPH3A.
复制标题
突触前先天性肌无力综合征，突触小泡稳态改变与 RPH3A 复合杂合序列变异有关。
DOI：
10.1002/mgg3.370
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发表时间：
2018
影响因子：
2
通讯作者：
Ferns,Michael
中科院分区：
文献类型：
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作者：
Maselli,RicardoA;Vázquez,Jessica;Schrumpf,Leah;Arredondo,Juan;Lara,Marian;Strober,JonathanB;Pytel,Peter;Wollmann,RobertL;Ferns,Michael
研究背景突触囊泡（SV）稳态的单基因缺陷与许多神经系统疾病有关，包括自闭症、癫痫和运动障碍。此外，异常囊泡胞吐已与几个内分泌dysfunctions.MethodsWe报告一个11岁的女孩与学习障碍，震颤，共济失调，短暂性高血糖症，肌肉疲劳性硫酸沙丁胺醇。单纤维肌电图证实神经肌肉传递失败。运动神经末梢的电子显微镜检查显示SV密度显著降低、含有SV的双膜结合囊、丰富的内体和退行性板层体。患者进行了全外显子组测序（WES）和相关的序列变异表达和研究在哺乳动物cellline.ResultsChromosomal微阵列研究和下一代测序（NGS）的线粒体DNA是unrevealed，然而，NGS的基因组DNA显示两个罕见的序列变异的基因编码rabphilin 3A（RPH 3A）。父系遗传变异体c.806 G>A（p.Arg269Gln）涉及连接区中保守残基的取代，而母系遗传变异体c.1390 G>T（p.Val464Leu）涉及高度保守的C2 A区中保守氨基酸的取代。表达研究表明，p.Arg269Gln强烈损害rabphilin 3a与14 - 3 - 3的结合，这是一种突触传递和可塑性的调节剂。与此相反，结合rabphilin 3a到14 - 3 - 3是只有轻微受损的p.Val464Leu，因此，p.Val464Leu的致病作用仍然unclear.ConclusionIn总结，我们报告一个病人的多系统神经系统疾病和改变SV调节归因于缺陷inRPH 3A，从而赠款进一步研究该基因在人类疾病的突触传递。
BackgroundMonogenic defects of synaptic vesicle (SV) homeostasis have been implicated in many neurologic diseases, including autism, epilepsy, and movement disorders. In addition, abnormal vesicle exocytosis has been associated with several endocrine dysfunctions.MethodsWe report an 11 year old girl with learning disabilities, tremors, ataxia, transient hyperglycemia, and muscle fatigability responsive to albuterol sulfate. Failure of neuromuscular transmission was confirmed by single fiber electromyography. Electron microscopy of motor nerve terminals revealed marked reduction in SV density, double‐membrane‐bound sacs containing SVs, abundant endosomes, and degenerative lamellar bodies. The patient underwent whole exome sequencing (WES) and relevant sequence variants were expressed and studied in a mammalian cell line.ResultsChromosomal microarray studies and next generation sequencing (NGS) of mitochondrial DNA were unrevealing; however, NGS of genomic DNA showed two rare sequence variants in the gene encoding rabphilin 3a(RPH3A). The paternally inherited variant c.806 G>A (p.Arg269Gln) involves a substitution of a conserved residue in the linker region, while the maternally inherited variant c.1390 G>T (p.Val464Leu) involves a conserved amino acid substitution in the highly conserved C2A region. Expression studies revealed that p.Arg269Gln strongly impairs the binding of rabphilin 3a to 14‐3‐3, which is a proposed regulator of synaptic transmission and plasticity. In contrast, the binding of rabphilin 3a to 14‐3‐3 is only marginally impaired by p.Val464Leu; thus, the pathogenic role of p.Val464Leu remains unclear.ConclusionIn summary, we report a patient with a multisystem neurologic disorder and altered SV regulation attributed to defects inRPH3A, which grants further studies of this gene in human disorders of synaptic transmission.