Spinocerebellar ataxia 27 with a novel nonsense variant (Lys177X) in FGF14
Spinocerebellar ataxia 27 with a novel nonsense variant (Lys177X) in FGF14
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DOI：
10.1016/j.ejmg.2018.07.005
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发表时间：
2019-03-01
影响因子：
1.9
通讯作者：
Shibata, Hiroki
中科院分区：
文献类型：
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作者：
Miura, Shiroh;Kosaka, Kengo;Shibata, Hiroki
脊髓小脑性共济失调27 （SCA27）是一种常染色体显性SCA，由成纤维细胞生长因子14 （FGF14）基因变异引起。我们检查了一位日本SCA患者，他已故的父亲也患有SCA。患者为一名63岁男性。他初中毕业，但没有接受进一步的教育。主要的主诉是缓慢进行性构音障碍和步态障碍，出现于47岁。他表现为病理性跳跃性动作障碍，跳跃性眼球运动侵犯，构音障碍，肢体和躯干共济失调。他的步态很宽，但他不需要拐杖。四肢肌肉力量完整。深肌腱反射正常或轻度减弱。病理反射缺失。他表现出下肢振动感轻度受损。无尿功能障碍。脑MRI显示小脑萎缩，未累及脑干。我们首先证实了SCAB 1-3、6-8、10、12、17、36和齿状小脑-苍白球萎缩基因中缺乏重复扩增。通过外显子组分析，我们在FGF14基因的第4外显子中发现了一个新的杂合变异（NM_004115, c.529A > T; Lys177X）。这种变异预计会产生一个截断的FGF14蛋白，缺乏肝素结合位点，这些位点可能会改变FGF14的活性。我们通过Sanger测序在502名日本健康个体中证实了该变体的缺失。在公共数据库中没有这种变体的记录。我们得出结论，FGF14的新变异是该患者SCA27的病因。
Spinocerebellar ataxia 27 (SCA27) is an autosomal dominant SCA caused by variants in the fibroblast growth factor 14 (FGF14) gene. We examined a Japanese SCA patient whose deceased father also suffered from SCA. The patient was a 63-year-old male. He graduated from junior high school but received no further education. The predominant complaint was slowly progressive dysarthria and gait disturbance, which appeared at age 47. He showed pathological saccadic dysmetria, saccadic intrusions into smooth pursuit eye movements, dysarthria, and limb and truncal ataxia. His gait was wide-based but he did not require a walking stick. Limb muscle strength was intact. Deep tendon reflexes were normal or slightly reduced. Pathological reflexes were absent. He demonstrated mildly impaired vibration sense in the lower limbs. There was no urinary dysfunction. Brain MRI showed cerebellar atrophy without brainstem involvement. We first confirmed the absence of repeat expansion in genes known to be responsible for SCAB 1-3, 6-8, 10, 12, 17, 36 and dentatorubral-pallidoluysian atrophy. By exome analysis, we identified a novel heterozygous variant (NM_004115, c.529A > T; Lys177X) in exon 4 of the FGF14 gene. This variant is expected to generate a truncated FGF14 protein lacking the heparin binding sites, those are likely to modify the activity of FGF14. We confirmed the absence of the variant in 502 healthy Japanese individuals by Sanger sequencing. There is no record of the variant in public databases. We conclude that the novel variation in FGF14 is causative for SCA27 in this patient.