背景:先前已报道GRN基因中的变异c.1414-1G>T可能在美洲大陆的西班牙裔受试者中致病。
方法:我们报告了五个西班牙血统的家族携带这种变体,包括临床,神经影像学,和实验室发现。
结果:表型明显不同,包括表现为额颞叶痴呆行为变异的病例,具有原发性进行性失语症的语义变异,患有快速进行性运动神经元疾病(病理记录),以震颤为主的帕金森病.仅在纯合携带者中发现了视网膜变性。离体剪接实验证实,突变c.1414-1G>T影响外显子的剪接,导致外显子11中20个氨基酸丢失.
结论:我们得出结论,变异c.1414-1G>TnGRN基因是致病性的,可以导致各种临床表现和基因剂量效应,可能有西班牙创始人的影响。
BACKGROUND: The variant c.1414-1G>T in the GRN gene has previously been reported as probably pathogenic in subjects of Hispanic origin in the American continent.
METHODS: We report 5 families of Spanish origin carrying this variant, including the clinical, neuroimaging, and laboratory findings.
RESULTS: Phenotypes were strikingly different, including cases presenting with behavioral variant frontotemporal dementia, semantic variant primary progressive aphasia, rapidly progressive motor neuron disease (pathologically documented), and tremor-dominant parkinsonism. Retinal degeneration has been found in homozygous carriers only. Ex vivo splicing assays confirmed that the mutation c.1414-1G>T affects the splicing of the exon, causing a loss of 20 amino acids in exon 11.
CONCLUSIONS: We conclude that variant c.1414-1G>T of the GRN gene is pathogenic, can lead to a variety of clinical presentations and to gene dosage effect, and probably has a Spanish founder effect.