Abstract：
DNM1 developmental and epileptic encephalopathy (DEE) is characterized by severe to profound intellectual disability, hypotonia, movement disorder, and refractory epilepsy, typically presenting with infantile spasms. Most of the affected individuals had de novo missense variants in DNM1. DNM1 undergoes alternative splicing that results in expression of six different transcript variants. One alternatively spliced region affects the tandemly arranged exons 10a and 10b, producing isoforms DNM1A and DNM1B, respectively. Pathogenic variants in the DNM1 coding region affect all transcript variants. Recently, a de novo DNM1 NM_001288739.1:c.1197-8G > A variant located in intron 9 has been reported in several unrelated individuals with DEE that causes in-frame insertion of two amino acids and leads to disease through a dominant-negative mechanism. We report on a patient with DEE and a de novo DNM1 variant NM_001288739.2:c.1197-46C > G in intron 9, upstream of exon 10a. By RT-PCR and Sanger sequencing using fibroblast-derived cDNA of the patient, we identified aberrantly spliced DNM1 mRNAs with exon 9 spliced to the last 45 nucleotides of intron 9 followed by exon 10a (NM_001288739.2:r.1196_1197ins[1197-1_1197-45]). The encoded DNM1A mutant is predicted to contain 15 novel amino acids between Ile398 and Arg399 [NP_001275668.1:p.(Ile398_Arg399ins15)] and likely functions in a dominant-negative manner, similar to other DNM1 mutants. Our data confirm the importance of the DNM1 isoform A for normal human brain function that is underscored by previously reported predominant expression of DMN1A transcripts in pediatric brain, functional differences of the mouse Dnm1a and Dnm1b isoforms, and the Dnm1 fitful mouse, an epilepsy mouse model.
摘要：
DNM1发育性和癫痫性脑病（DEE）的特征是严重至严重的智力残疾，低张力,运动障碍,和难治性癫痫，通常表现为婴儿痉挛。大多数受影响的个体在DNM1中具有从头错义变体。DNM1经历选择性剪接，导致六种不同的转录变体表达。一个交替剪接的区域影响串联排列的外显子10a和10b，产生亚型DNM1A和DNM1B，分别。DNM1编码区中的致病性变体影响所有转录物变体。最近,a从头DNM1NM_001288739.1：c.1197-8G>在几个无关的DEE个体中报道了位于内含子9中的变体，该变体导致两个氨基酸的框内插入，并通过显性负机制导致疾病。我们报道了一名患有DEE和从头DNM1变体NM_001288739.2的患者：c.1197-46C>G在外显子10a上游的内含子9中。通过RT-PCR和Sanger测序，使用患者的成纤维细胞来源的cDNA，我们鉴定了异常剪接的DNM1mRNA，外显子9剪接到内含子9的最后45个核苷酸，然后是外显子10a（NM_001288739.2：r.1196_1197ins[1197-1_1197-45]）。预测编码的DNM1A突变体在Ile398和Arg399之间含有15个新氨基酸[NP_001275668.1:p.（Ile398_Arg399ins15）]和可能以显性否定的方式运行，与其他DNM1突变体相似。我们的数据证实了DNM1亚型A对正常人脑功能的重要性，这是以前报道的DMN1A转录本在小儿脑中的主要表达所强调的。小鼠Dnm1a和Dnm1b亚型的功能差异，和Dnm1适当的鼠标，癫痫小鼠模型。
