Cerebellar ataxia-dominant phenotype in patients with ERCC4 mutations
Cerebellar ataxia-dominant phenotype in patients with ERCC4 mutations
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DOI：
10.1038/s10038-017-0408-5
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发表时间：
2018-04-01
影响因子：
3.5
通讯作者：
Tanaka, Fumiaki
中科院分区：
文献类型：
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作者：
Doi, Hiroshi;Koyano, Shigeru;Tanaka, Fumiaki
常染色体隐性遗传性小脑共济失调（ACAA）是临床和遗传异质性神经系统疾病。通过对日本ARCA患者的全外显子组测序，我们从ERCC 4双等位基因突变的无关家族中确定了三名索引患者。已知ERCC 4突变可导致着色性干皮病互补组F（XP-F）、Cockayne综合征和范可尼贫血表型。所有的病人都表现出非常缓慢的进行性小脑共济失调和认知能力下降，伴有舞蹈样不自主运动，年轻的青少年或中年发病。脑MRI显示萎缩，包括小脑和脑干。值得注意的是，皮肤症状非常轻度：暴露皮肤区域存在正常至非常轻度的色素沉着和/或可疑的病理性晒伤病史。然而，从病人的成纤维细胞的非程序性DNA合成试验显示核苷酸切除修复受损。最近通过对高加索小脑共济失调患者的遗传分析发现了类似的表型。我们的研究结果证实，双等位基因ERCC 4突变导致小脑共济失调显性表型与轻度皮肤症状，可能占很高比例的遗传原因ARCA在日本，其中XP-F是普遍存在的。
Autosomal recessive cerebellar ataxias (ARCAs) are clinically and genetically heterogeneous neurological disorders. Through whole-exome sequencing of Japanese ARCA patients, we identified three index patients from unrelated families who had biallelic mutations in ERCC4. ERCC4 mutations have been known to cause xeroderma pigmentosum complementation group F (XP-F), Cockayne syndrome, and Fanconi anemia phenotypes. All of the patients described here showed very slowly progressive cerebellar ataxia and cognitive decline with choreiform involuntary movement, with young adolescent or midlife onset. Brain MRI demonstrated atrophy that included the cerebellum and brainstem. Of note, cutaneous symptoms were very mild: there was normal to very mild pigmentation of exposed skin areas and/or an equivocal history of pathological sunburn. However, an unscheduled DNA synthesis assay of fibroblasts from the patient revealed impairment of nucleotide excision repair. A similar phenotype was very recently recognized through genetic analysis of Caucasian cerebellar ataxia patients. Our results confirm that biallelic ERCC4 mutations cause a cerebellar ataxia-dominant phenotype with mild cutaneous symptoms, possibly accounting for a high proportion of the genetic causes of ARCA in Japan, where XP-F is prevalent.