De novo in-frame deletions and duplications in the SPTAN1 gene, encoding the non-erythrocyte αII spectrin, have been associated with severe West syndrome with hypomyelination and pontocerebellar atrophy. We aimed at comprehensively delineating the phenotypic spectrum associated with SPTAN1 mutations. Using different molecular genetic techniques, we identified 20 patients with a pathogenic or likely pathogenic SPTAN1 variant and reviewed their clinical, genetic and imaging data. SPTAN1 de novo alterations included seven unique missense variants and nine in-frame deletions/duplications of which 12 were novel. The recurrent three-amino acid duplication p.(Asp2303_Leu2305dup) occurred in five patients. Our patient cohort exhibited a broad spectrum of neurodevelopmental phenotypes, comprising six patients with mild to moderate intellectual disability, with or without epilepsy and behavioural disorders, and 14 patients with infantile epileptic encephalopathy, of which 13 had severe neurodevelopmental impairment and four died in early childhood. Imaging studies suggested that the severity of neurological impairment and epilepsy correlates with that of structural abnormalities as well as the mutation type and location. Out of seven patients harbouring mutations outside the α/β spectrin heterodimerization domain, four had normal brain imaging and three exhibited moderately progressive brain and/or cerebellar atrophy. Twelve of 13 patients with mutations located within the spectrin heterodimer contact site exhibited severe and progressive brain, brainstem and cerebellar atrophy, with hypomyelination in most. We used fibroblasts from five patients to study spectrin aggregate formation by Triton-X extraction and immunocytochemistry followed by fluorescence microscopy. αII/βII aggregates and αII spectrin in the insoluble protein fraction were observed in fibroblasts derived from patients with the mutations p.(Glu2207del), p.(Asp2303_Leu2305dup) and p.(Arg2308_Met2309dup), all falling in the nucleation site of the α/β spectrin heterodimer region. Molecular modelling of the seven SPTAN1 amino acid changes provided preliminary evidence for structural alterations of the A-, B- and/or C-helices within each of the mutated spectrin repeats. We conclude that SPTAN1-related disorders comprise a wide spectrum of neurodevelopmental phenotypes ranging from mild to severe and progressive. Spectrin aggregate formation in fibroblasts with mutations in the α/β heterodimerization domain seems to be associated with a severe neurodegenerative course and suggests that the amino acid stretch from Asp2303 to Met2309 in the α20 repeat is important for α/β spectrin heterodimer formation and/or αII spectrin function.

中文翻译：

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描绘SPTAN1相关表型：从单纯性癫痫到进展性脑萎缩性脑病

从头的框内缺失和重复在SPTAN1基因，编码非红细胞血影αII已经与hypomyelination和脑桥小脑萎缩严重West综合征相关联。我们旨在全面描述与SPTAN1突变相关的表型谱。我们使用不同的分子遗传技术，鉴定了20名具有致病性或可能致病性SPTAN1变异的患者，并回顾了他们的临床，遗传和影像学数据。SPTAN1从头改变包括七个独特的错义变体和九个框内缺失/重复，其中十二个是新颖的。复发性三氨基酸重复p。（Asp2303_Leu2305dup）发生在五例患者中。我们的患者队列表现出广泛的神经发育表型，包括6名轻度至中度智力残疾，有无癫痫和行为障碍患者以及14例婴儿癫痫性脑病患者，其中13例患有严重的神经发育障碍，其中4例在儿童早期死亡。影像学研究表明，神经功能障碍和癫痫的严重程度与结构异常以及突变的类型和位置有关。在7名患者的α/β血影蛋白异二聚体结构域之外发生突变的患者中，4例大脑影像学正常，3例中度进行性脑和/或小脑萎缩。位于血影蛋白异二聚体接触位点内的13位突变患者中，有12位表现出严重的进行性脑，脑干和小脑萎缩，大多数患者出现髓鞘减少。我们使用了来自五名患者的成纤维细胞，通过Triton-X提取，免疫细胞化学和荧光显微镜研究了血影蛋白聚集体的形成。在源自突变p。（Glu2207del），p。（Asp2303_Leu2305dup）和p。（Arg2308_Met2309dup）的患者的成纤维细胞中观察到不溶蛋白级分中的αII/βII聚集体和αII血影蛋白，均位于α/的成核位点β血影蛋白异二聚体区域。七个分子的建模 位于血影蛋白异二聚体接触位点内的13位突变患者中，有12位表现出严重的进行性脑，脑干和小脑萎缩，大多数患者出现髓鞘减少。我们使用了来自五名患者的成纤维细胞，通过Triton-X提取，免疫细胞化学和荧光显微镜研究了血影蛋白聚集体的形成。在源自突变p。（Glu2207del），p。（Asp2303_Leu2305dup）和p。（Arg2308_Met2309dup）的患者的成纤维细胞中观察到不溶蛋白级分中的αII/βII聚集体和αII血影蛋白，均位于α/的成核位点β血影蛋白异二聚体区域。七个分子的建模 位于血影蛋白异二聚体接触位点内的13位突变患者中，有12位表现出严重的进行性脑，脑干和小脑萎缩，大多数患者出现髓鞘减少。我们使用了来自五名患者的成纤维细胞，通过Triton-X提取，免疫细胞化学和荧光显微镜研究了血影蛋白聚集体的形成。在源自突变p。（Glu2207del），p。（Asp2303_Leu2305dup）和p。（Arg2308_Met2309dup）的患者的成纤维细胞中观察到不溶蛋白级分中的αII/βII聚集体和αII血影蛋白，均位于α/的成核位点β血影蛋白异二聚体区域。七个分子的建模 我们使用了来自五名患者的成纤维细胞，通过Triton-X提取，免疫细胞化学和荧光显微镜研究了血影蛋白聚集体的形成。在源自突变p。（Glu2207del），p。（Asp2303_Leu2305dup）和p。（Arg2308_Met2309dup）的患者的成纤维细胞中观察到不溶蛋白级分中的αII/βII聚集体和αII血影蛋白，均位于α/的成核位点β血影蛋白异二聚体区域。七个分子的建模 我们使用了来自五名患者的成纤维细胞，通过Triton-X提取，免疫细胞化学和荧光显微镜研究了血影蛋白聚集体的形成。在源自突变p。（Glu2207del），p。（Asp2303_Leu2305dup）和p。（Arg2308_Met2309dup）的患者的成纤维细胞中观察到不溶蛋白级分中的αII/βII聚集体和αII血影蛋白，均位于α/的成核位点β血影蛋白异二聚体区域。七个分子的建模 全部落在α/β血影蛋白异二聚体区域的成核位点。七个分子的建模 全部落在α/β血影蛋白异二聚体区域的成核位点。七个分子的建模SPTAN1氨基酸的变化为每个突变的血影蛋白重复序列​​中A，B和/或C螺旋的结构改变提供了初步证据。我们得出结论，与SPTAN1相关的疾病包括从轻度到重度和进行性的广泛的神经发育表型。在成纤维细胞中具有α/β异二聚体结构域突变的血影蛋白聚集体形成似乎与严重的神经退行性病程有关，这表明α20重复序列中从Asp2303到Met2309的氨基酸延伸对于α/β血影蛋白异二聚体的形成和/或αII血影蛋白功能。