From the Genetics and Rare Diseases Research Division (V.M., G.C., T.R., M.D.N., A.C., F.P., R.C., M.T.), Ospedale Pediatrico Bambino Gesù; Department of Oncology and Molecular Medicine (E.F., S.M.) and Confocal Microscopy Unit (S.C.), Core Facilities, Istituto Superiore di Sanità, Rome, Italy; Center for Human Disease Modeling (Z.K., M.M.K., N.K.), Duke University School of Medicine, Durham, NC; Institutes of Neurology (G.P., S.S.) and Nuclear Medicine (D.D.G.), Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy; Department of Genetics (H.G., N.M.), Faculty of Science, Shahid Chamran University of Ahvaz; Narges Medical Genetics and Prenatal Diagnosis Laboratory (H.G., N.M., A. Sedaghat, J.Z., G.R.S.), Kianpars, Ahvaz; Research and Clinical Center for Infertility (M.D.), Yazd Reproductive Sciences Institute, Medical Genetics Research Centre (M.D., M.Y.V.M.), and Department of Medical Genetics (M.Y.V.M.), Shahid Sadoughi University of Medical Sciences, Yazd, Iran; Department of Experimental Medicine (A.T., V.C.), Università "Sapienza," Rome, Italy; Genetics and Molecular Cell Sciences Research Centre (Y.J., R.M.), St. George's University of London, UK; Department of Paediatric Neurology (R.A.M.), Golestan Medical, Educational, and Research Center, and Department of Medical Genetics (G.R.S.), Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Iran; University of Exeter Medical School (A.R.J.), RILD, Royal Devon & Exeter Hospital, UK; and Department of Neurology (A. Sherafat), Kerman University of Medical Sciences, Iran.
Neurology. 2018 Jul 24;91(4):e319-e330. doi: 10.1212/WNL.0000000000005869. Epub 2018 Jun 29.
To characterize clinically and molecularly an early-onset, variably progressive neurodegenerative disorder characterized by a cerebellar syndrome with severe ataxia, gaze palsy, dyskinesia, dystonia, and cognitive decline affecting 11 individuals from 3 consanguineous families.
We used whole-exome sequencing (WES) (families 1 and 2) and a combined approach based on homozygosity mapping and WES (family 3). We performed in vitro studies to explore the effect of the nontruncating mutation on protein function and the effect of impaired SQSTM1 function on autophagy. We analyzed the consequences of sqstm1 down-modulation on the structural integrity of the cerebellum in vivo using zebrafish as a model.
We identified 3 homozygous inactivating variants, including a splice site substitution (c.301+2T>A) causing aberrant transcript processing and accelerated degradation of a resulting protein lacking exon 2, as well as 2 truncating changes (c.875_876insT and c.934_936delinsTGA). We show that loss of SQSTM1 causes impaired production of ubiquitin-positive protein aggregates in response to misfolded protein stress and decelerated autophagic flux. The consequences of sqstm1 down-modulation on the structural integrity of the cerebellum in zebrafish documented a variable but reproducible phenotype characterized by cerebellum anomalies ranging from depletion of axonal connections to complete atrophy. We provide a detailed clinical characterization of the disorder; the natural history is reported for 2 siblings who have been followed up for >20 years.
This study offers an accurate clinical characterization of this recently recognized neurodegenerative disorder caused by biallelic inactivating mutations in and links this phenotype to defective selective autophagy.
描述一种早发性、进行性神经退行性疾病，其特征为小脑综合征，伴有严重的共济失调、眼球运动障碍、运动障碍、肌张力障碍和认知能力下降，影响来自 3 个近亲家庭的 11 个人。
我们使用全外显子组测序（WES）（家系 1 和 2）和一种基于纯合子作图和 WES 的组合方法（家系 3）。我们进行了体外研究，以探索非截断突变对蛋白功能的影响以及 SQSTM1 功能障碍对自噬的影响。我们使用斑马鱼作为模型，分析 sqstm1 下调对小脑结构完整性的体内后果。
我们鉴定出 3 个纯合失活变体，包括一个剪接位点取代（c.301+2T>A），导致异常的转录产物加工和导致缺乏外显子 2 的蛋白质的加速降解，以及 2 个截断变化（c.875_876insT 和 c.934_936delinsTGA）。我们表明，SQSTM1 的缺失导致在应对错误折叠蛋白应激时产生的泛素阳性蛋白聚集体减少，并且自噬流减慢。sqstm1 下调对斑马鱼小脑结构完整性的影响记录了一种可变但可重复的表型，特征为小脑异常，从轴突连接缺失到完全萎缩不等。我们对该疾病进行了详细的临床特征描述；报告了 2 个接受随访超过 20 年的同胞的自然病史。
本研究提供了这种最近发现的神经退行性疾病的准确临床特征描述，其原因是 和 中的双等位基因失活突变，并将这种表型与选择性自噬缺陷联系起来。
