Tracing neuropathological signatures: TARDBP and C9orf72 double mutations in a Sicilian family.

IF 3.2 2区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Pegah Masrori, Sandra O Tomé, Lieselot Dedeene, Gauthier Remiche, Hilde Van Esch, Dietmar Rudolf Thal, Philip Van Damme
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引用次数: 0

Abstract

Co-occurrence of double heterozygosity in TARDBP and C9ORF72 is exceedingly rare in amyotrophic lateral sclerosis. While TARDBP mutations and C9ORF72 hexanucleotide repeat expansions have each been independently implicated in disease pathogenesis, their combined effect on disease progression and neuropathology remains unclear. We present the first study documenting a patient harboring both a TARDBP mutation and a C9ORF72 expansion, with comprehensive postmortem data available, to elucidate any additive or synergistic effects on disease course and pathological burden. Detailed clinical assessments tracked the patient's progression, and neuropathological examination was performed postmortem. The presence and extent of TDP-43 pathology and other hallmark features were evaluated and compared to known patterns in carriers of isolated C9ORF72 mutations. The patient's clinical trajectory and pathological findings did not show evidence of a more aggressive disease course or heightened pathological burden attributable to the additional TARDBP mutation. Instead, the disease manifested in a manner consistent with other C9ORF72 carriers, suggesting that double heterozygosity do not necessarily exacerbate ALS pathology.

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追踪神经病理特征:西西里家族的TARDBP和C9orf72双突变。
在肌萎缩性侧索硬化症中,TARDBP和C9ORF72同时出现双杂合性是非常罕见的。虽然TARDBP突变和C9ORF72六核苷酸重复扩增各自独立参与疾病发病机制,但它们对疾病进展和神经病理的综合影响尚不清楚。本研究首次记录了一名同时携带TARDBP突变和C9ORF72扩增的患者,并提供了全面的尸检数据,以阐明疾病病程和病理负担中的任何附加或协同作用。详细的临床评估跟踪了患者的进展,并在死后进行了神经病理学检查。评估TDP-43病理和其他标志性特征的存在和程度,并将其与分离的C9ORF72突变携带者的已知模式进行比较。患者的临床轨迹和病理结果没有显示出由于额外的TARDBP突变而导致更严重的病程或加重的病理负担的证据。相反,该疾病的表现方式与其他C9ORF72携带者一致,这表明双杂合性并不一定会加重ALS病理。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Human molecular genetics
Human molecular genetics 生物-生化与分子生物学
CiteScore
6.90
自引率
2.90%
发文量
294
审稿时长
2-4 weeks
期刊介绍: Human Molecular Genetics concentrates on full-length research papers covering a wide range of topics in all aspects of human molecular genetics. These include: the molecular basis of human genetic disease developmental genetics cancer genetics neurogenetics chromosome and genome structure and function therapy of genetic disease stem cells in human genetic disease and therapy, including the application of iPS cells genome-wide association studies mouse and other models of human diseases functional genomics computational genomics In addition, the journal also publishes research on other model systems for the analysis of genes, especially when there is an obvious relevance to human genetics.
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