Delineating SPTAN1 associated phenotypes: from isolated epilepsy to encephalopathy with progressive brain atrophy
Delineating SPTAN1 associated phenotypes: from isolated epilepsy to encephalopathy with progressive brain atrophy
复制标题
DOI：
10.1093/brain/awx195
复制
发表时间：
2017-09-01
期刊：
影响因子：
14.5
通讯作者：
Guerrini, Renzo
中科院分区：
文献类型：
--
作者：
Syrbe, Steffen;Harms, Frederike L.;Guerrini, Renzo
编码非红细胞αII血影蛋白的SPTAN1基因中的从头框内缺失和重复，与伴有髓鞘形成不良和脑桥小脑萎缩的严重West综合征相关。我们旨在全面描绘与SPTAN1突变相关的表型谱。利用不同的分子遗传学技术，我们确定了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7种独特的错义变异和9种框内缺失/重复，其中12种是新的。反复出现的三个氨基酸重复p.(Asp2303_Leu2305dup)发生在5名患者中。我们的患者队列表现出广泛的神经发育表型，包括6名有轻度至中度智力障碍（伴有或不伴有癫痫和行为障碍）的患者，以及14名婴儿癫痫性脑病患者，其中13名有严重的神经发育障碍，4名在幼儿期死亡。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的严重程度以及突变类型和位置相关。在α/β血影蛋白异二聚化结构域之外携带突变的7名患者中，4名脑部影像学正常，3名表现出中度进行性脑和/或小脑萎缩。13名在血影蛋白异二聚体接触位点发生突变的患者中有12名表现出严重且进行性的脑、脑干和小脑萎缩，大多数伴有髓鞘形成不良。我们使用来自5名患者的成纤维细胞，通过Triton - X提取和免疫细胞化学，然后进行荧光显微镜检查来研究血影蛋白聚集体的形成。在来自具有p.(Glu2207del)、p.(Asp2303_Leu2305dup)和p.(Arg2308_Met2309dup)突变的患者的成纤维细胞中观察到αII/βII聚集体和不溶性蛋白组分中的αII血影蛋白，这些突变都位于α/β血影蛋白异二聚体区域的成核位点。对7种SPTAN1氨基酸变化的分子建模为每个突变的血影蛋白重复序列内的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，SPTAN1相关疾病包括从轻度到重度和进行性的广泛神经发育表型谱。在α/β异二聚化结构域有突变的成纤维细胞中血影蛋白聚集体的形成似乎与严重的神经退行性病程相关，并表明α20重复序列中从Asp2303到Met2309的氨基酸序列对α/β血影蛋白异二聚体形成和/或αII血影蛋白功能很重要。
De novo in-frame deletions and duplications in the SPTAN1 gene, encoding the non-erythrocyte aII 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 alpha/beta 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. alpha II/beta II aggregates and aII 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 alpha/beta 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 alpha/beta heterodimerization domain seems to be associated with a severe neurodegenerative course and suggests that the amino acid stretch from Asp2303 to Met2309 in the alpha 20 repeat is important for alpha/beta spectrin heterodimer formation and/or alpha II spectrin function.