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.

DNM1发育性癫痫性脑病 (DEE) 的特点是严重至极重度智力障碍、肌张力低下、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中存在从头错义变异。DNM1经历选择性剪接，导致六种不同转录物变体的表达。一个选择性剪​​接区域影响串联排列的外显子 10a 和 10b，分别产生同工型 DNM1A 和 DNM1B。DNM1编码区的致病变异影响所有转录物变异。最近，在几个不相关的 DEE 个体中报道了一种新的 DNM1 NM_001288739.1:c.1197-8G > 位于内含子 9 的变体，该变体导致两个氨基酸的框内插入，并通过显性失活导致疾病机制。我们报告了一名 DEE 患者，其DNM1新生变异 NM_001288739.2:c.1197-46C > G 位于外显子 10a 上游的内含子 9 中。通过使用患者成纤维细胞衍生的 cDNA 进行 RT-PCR 和 Sanger 测序，我们鉴定出异常剪接的DNM1 mRNA，其中外显子 9 剪接到内含子 9 的最后 45 个核苷酸，随后是外显子 10a (NM_001288739.2:r.1196_1197ins[1197-1_1197 -45]）。编码的 DNM1A 突变体预计在 Ile398 和 Arg399 之间包含 15 个新氨基酸 [NP_001275668.1:p.(Ile398_Arg399ins15)]，并且可能以显性失活方式发挥作用，与其他 DNM1 突变体类似。我们的数据证实了 DNM1 同工型 A 对于正常人脑功能的重要性，之前报道的DMN1A转录物在儿科大脑中的主要表达、小鼠 Dnm1a 和 Dnm1b 同工型的功能差异以及Dnm1间歇性小鼠（一种癫痫小鼠模型）强调了这一点。