Clinical and Molecular Aspects of Senataxin Mutations in Amyotrophic Lateral Sclerosis 4.
Clinical and Molecular Aspects of Senataxin Mutations in Amyotrophic Lateral Sclerosis 4.
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DOI：
10.1002/ana.25681
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发表时间：
2020-04
影响因子：
11.2
通讯作者：
Cheung VG
中科院分区：
文献类型：
--
作者：
Grunseich C;Patankar A;Amaya J;Watts JA;Li D;Ramirez P;Schindler AB;Fischbeck KH;Cheung VG
确定senataxin（SETX）基因突变导致的肌萎缩侧索硬化4型（ALS 4）患者的临床和分子特征，并开发评估SETX变体的工具。我们的研究涉及32例患者，包括31例SETX突变在c.1166 T>C（p.Leu389Ser）和1例突变在c.1153 G>A（p.Glu385Lys）。患者的临床表征包括神经系统检查、血液检查、磁共振成像（MRI）和双能X线吸收测定法（DEXA）。获得成纤维细胞和运动神经元以模拟疾病并表征senataxin功能的分子改变。我们报告ALS 4的主要临床特征。实验室分析显示Leu 389 Ser ALS 4队列中血清肌酸激酶和肌酐的改变。MRI显示下肢肌肉脂肪分数增加，这与疾病持续时间相关（大腿脂肪分数R2 = 0.35，p = 0.01;小腿脂肪分数R2 = 0.49，p < 0.01）。DEXA测量显示下肢比上肢受影响更大（平均脂肪z评分分别为2.1和0.6）。SETX功能的细胞测定证实，与Leu 389 Ser突变一样，Glu 385 Lys变体导致R环减少，可能来自功能的获得。我们确定了ALS 4的临床实验室和放射学特征，因此应监测其疾病进展。患者源性细胞中R环水平的分子表征提供了对疾病病理学的深入了解，并提供了评价SETX基因中候选突变致病性的测定。神经网络2020;87：547-555
To determine the clinical and molecular features in patients with amyotrophic lateral sclerosis 4 (ALS4) due to mutations in the senataxin (SETX) gene and to develop tools for evaluating SETX variants. Our study involved 32 patients, including 31 with mutation in SETX at c.1166 T>C (p.Leu389Ser) and 1 with mutation at c.1153 G>A (p.Glu385Lys). Clinical characterization of the patients included neurological examination, blood tests, magnetic resonance imaging (MRI), and dual‐energy x‐ray absorptiometry (DEXA). Fibroblasts and motor neurons were obtained to model the disease and characterize the molecular alteration in senataxin function. We report key clinical features of ALS4. Laboratory analysis showed alteration of serum creatine kinase and creatinine in the Leu389Ser ALS4 cohort. MRI showed increased muscle fat fraction in the lower extremities, which correlates with disease duration (thigh fat fraction R 2 = 0.35, p = 0.01; lower leg fat fraction R 2 = 0.49, p < 0.01). DEXA measurements showed lower extremities are more affected than upper extremities (average fat z scores of 2.1 and 0.6, respectively). A cellular assay for SETX function confirmed that like the Leu389Ser mutation, the Glu385Lys variant leads to a decrease in R loops, likely from a gain of function. We identified clinical laboratory and radiological features of ALS4, and hence they should be monitored for disease progression. The molecular characterization of R‐loop levels in patient‐derived cells provides insight into the disease pathology and assays to evaluate the pathogenicity of candidate mutations in the SETX gene. ANN NEUROL 2020;87:547–555
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Senataxin 突变和肌萎缩侧索硬化症。
DOI：
10.3109/17482968.2010.545952
发表时间：
2011-05
期刊：
Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases
影响因子：
--
作者：
Hirano M;Quinzii CM;Mitsumoto H;Hays AP;Roberts JK;Richard P;Rowland LP
通讯作者：
Rowland LP
影响因子：
56.9
作者：
Kwiatkowski, T. J., Jr.;Bosco, D. A.;Brown, R. H., Jr.
通讯作者：
Brown, R. H., Jr.
影响因子：
--
作者：
Avemaria, Francesca;Lunetta, Christian;Corbo, Massimo
通讯作者：
Corbo, Massimo
影响因子：
14.9
作者：
Hu, Zonglin;Zhang, Aixia;Leppla, Stephen H.
通讯作者：
Leppla, Stephen H.
影响因子：
4.8
作者：
Haruki, M;Noguchi, E;Crouch, RJ
通讯作者：
Crouch, RJ