New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49).
New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49).
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DOI：
10.1093/braincomms/fcac030
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发表时间：
2022
影响因子：
4.8
通讯作者：
Matilla-Dueñas A
中科院分区：
文献类型：
--
作者：
Corral-Juan M;Casquero P;Giraldo-Restrepo N;Laurie S;Martinez-Piñeiro A;Mateo-Montero RC;Ispierto L;Vilas D;Tolosa E;Volpini V;Alvarez-Ramo R;Sánchez I;Matilla-Dueñas A
脊髓小脑性共济失调是一组高度异质性的遗传性运动障碍，临床特征为进行性小脑性共济失调，并伴有其他不同的临床体征。大量的相关基因和潜在的遗传缺陷证明了这种遗传异质性。在这项研究中，我们描述了来自梅诺卡的一个西班牙五代家庭的九名成员中的一种新的脊髓小脑性共济失调亚型，患者表现为共济失调、眼球震颤、构音障碍、多发性神经病、锥体体征、小脑萎缩和独特的脑脱髓鞘。受影响的个体以水平和垂直注视诱发的眼球震颤和反射亢进为首发临床症状，发病年龄从12岁到60岁不等。神经生理学研究显示中度轴索感觉性多发性神经病，交感神经皮肤反应改变，主要发生在下肢。我们确定SAMD9L基因中的c.1877C >； T(p.Ser626Leu)致病变异是致病的遗传缺陷，具有显著的对数优势分数(Zmax = 3.43；θ = 0.00；P <； 3.53 × 10−5)。我们证明了人类SAMD9L蛋白的线粒体位置，以及它在患者成纤维细胞中的水平降低，以及线粒体的扰动。此外，斑马鱼中的突变SAMD9L损害了行动能力和前庭/感觉功能。本研究描述了一种新的脊髓小脑性共济失调亚型，SCA49是由SAMD9L突变引起的，它触发了线粒体的改变，表明SAMD9L在神经运动和感觉功能中发挥了作用。Corral-Juan等人。描述一种新的显性遗传性脊髓小脑性共济失调亚型SCA49，由SAMD9L突变引起，其特征是多发性神经病，以凝视诱发的眼球震颤和反射亢进为初始临床症状的独特的脑脱髓鞘。这项研究证明了人类SAMD9L蛋白的线粒体位置触发了线粒体和溶酶体的改变。
Spinocerebellar ataxias consist of a highly heterogeneous group of inherited movement disorders clinically characterized by progressive cerebellar ataxia variably associated with additional distinctive clinical signs. The genetic heterogeneity is evidenced by the myriad of associated genes and underlying genetic defects identified. In this study, we describe a new spinocerebellar ataxia subtype in nine members of a Spanish five-generation family from Menorca with affected individuals variably presenting with ataxia, nystagmus, dysarthria, polyneuropathy, pyramidal signs, cerebellar atrophy and distinctive cerebral demyelination. Affected individuals presented with horizontal and vertical gaze-evoked nystagmus and hyperreflexia as initial clinical signs, and a variable age of onset ranging from 12 to 60 years. Neurophysiological studies showed moderate axonal sensory polyneuropathy with altered sympathetic skin response predominantly in the lower limbs. We identified the c.1877C > T (p.Ser626Leu) pathogenic variant within the SAMD9L gene as the disease causative genetic defect with a significant log-odds score (Zmax = 3.43; θ = 0.00; P < 3.53 × 10−5). We demonstrate the mitochondrial location of human SAMD9L protein, and its decreased levels in patients’ fibroblasts in addition to mitochondrial perturbations. Furthermore, mutant SAMD9L in zebrafish impaired mobility and vestibular/sensory functions. This study describes a novel spinocerebellar ataxia subtype caused by SAMD9L mutation, SCA49, which triggers mitochondrial alterations pointing to a role of SAMD9L in neurological motor and sensory functions. Corral-Juan et al. describe a novel dominantly inherited spinocerebellar ataxia subtype, SCA49, caused by SAMD9L mutation characterized by polyneuropathy, distinctive cerebral demyelination with gaze-evoked nystagmus and hyperreflexia as initial clinical signs. The study demonstrates the mitochondrial location of human SAMD9L protein triggering mitochondrial and lysosomal alterations.
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影响因子：
--
作者：
Christova, Peka;Anderson, John H.;Gomez, Christopher M.
通讯作者：
Gomez, Christopher M.
影响因子：
14.5
作者：
Chung, MY;Lu, YC;Soong, BW
通讯作者：
Soong, BW
DOI：
10.1124/jpet.112.192138
发表时间：
2012-09-01
影响因子：
3.5
作者：
Johri, Ashu;Beal, M. Flint
通讯作者：
Beal, M. Flint
影响因子：
16.2
作者：
Di Donato, Vincenzo;De Santis, Flavia;Del Bene, Filippo
通讯作者：
Del Bene, Filippo
DOI：
10.1002/ajmg.10361
发表时间：
2002-05-08
期刊：
AMERICAN JOURNAL OF MEDICAL GENETICS
影响因子：
--
作者：
Brkanac, Z;Fernandez, M;Raskind, WH
通讯作者：
Raskind, WH