Truncating mutations in YIF1B cause a progressive encephalopathy with various degrees of mixed movement disorder, microcephaly, and epilepsy
Truncating mutations in YIF1B cause a progressive encephalopathy with various degrees of mixed movement disorder, microcephaly, and epilepsy
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DOI：
10.1007/s00401-020-02128-8
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发表时间：
2020-01-31
影响因子：
12.7
通讯作者：
Kaya, Namik
中科院分区：
文献类型：
--
作者：
AlMuhaizea, Mohammed;AlMass, Rawan;Kaya, Namik
几种细胞内蛋白质参与介导真核细胞中蛋白质和脂质货物从内质网 (ER) 到高尔基体 (GA) 的囊泡运输。 ER 和 GA 之间的膜运输错误与大脑疾病有关 [1, 7]，表明这些过程对于神经元生物发生至关重要。这些过程中的一个重要蛋白质是 YIF1B，一种细胞内 314 个残基的跨膜蛋白。来自 Yif1B 敲除 (KO) 小鼠的海马神经元表明，Yif1B 与顺行运输和高尔基体结构有关 [1]，其中 Yif1b 的耗竭导致锥体神经元中 GA 的解体、碎片和体积减小。在此，我们描述了来自 5 个无关家族的 6 名患者，这些患者患有严重的发育和运动迟缓，伴有肌张力障碍、吞咽困难、肌张力减退、癫痫和小头畸形，并且通过全外显子组测序 (WES) 发现 YIF1B 中的纯合截短变异，将 YIF1B 鉴定为人类中的一种新疾病基因（图 1，补充图 1，补充表 1，详细临床信息的在线资源）。临床检查显示，所有患者妊娠和分娩均无异常，无重大畸形特征。在婴儿期就注意到肌张力低下和整体发育迟缓，微笑和部分牙牙学语是他们获得的最好的社交和语言技能。如果没有头部控制、滚动或坐着，运动发育仍然受到严重影响。 4 名个体在 2-3 岁时开始出现肢体舞蹈样运动，并在 4-8 岁时演变成轴向和肢体肌张力障碍并伴有运动障碍。肌张力障碍对左旋多巴或卡比多巴无反应，但部分改善
Several intracellular proteins are involved in mediating vesicular transport of protein and lipid cargo from the endoplasmic reticulum (ER) to the Golgi apparatus (GA) in eukaryotic cells. Errors in membrane trafficking between ER and GA have been implicated in brain disorders [1, 7], showing that these processes are critical for neuronal biogenesis. An important protein in these processes is YIF1B, an intracellular 314-residue transmembrane protein. Hippocampal neurons from Yif1B knockout (KO) mice showed that Yif1B is implicated in anterograde trafficking and Golgi architecture [1], where depletion of Yif1b caused disorganization, fragmentation, and volume reduction of the GA in pyramidal neurons.Here we describe six patients from five unrelated families presenting with profound developmental and motor delay with dystonia, dysphagia, hypotonia, epilepsy and microcephaly, and homozygous truncating variants in YIF1B encountered by whole exome sequencing (WES), identifying YIF1B as a novel disease gene in humans (Fig. 1, Supplementary Fig. 1, Supplementary Table 1, online resource for detailed clinical information). Clinical examinations revealed that all patients had an unremarkable pregnancy and birth, and no major dysmorphic features. Hypotonia and global developmental delay were noticed in infancy with smiling and partial babbling as their best achieved social and language skills. Motor development remained profoundly affected without head control, rolling or sitting. By age 2–3 years distal, limb choreiform movements started in four individuals which evolved into axial and limb dystonia with dyskinesia by the age of 4–8 years. Dystonia was unresponsive to levodopa or carbidopa but partially improved