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Degenerative Diseases of the Nervous System
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
James A. Mastrianni, Elizabeth A. Harris
The discovery that residues in ATXN1 outside of the polyglutamine tract are crucial for pathogenesis hints that alterations in the normal function of this protein are linked to its toxicity. Biochemical and genetic studies provide evidence that the polyglutamine expansion enhances interactions that are normally regulated by phosphorylation at the amino acid serine in position 776, and a subsequent alteration in its interaction with other cellular proteins.24
Investigating TBP CAG/CAA trinucleotide repeat expansions in a Taiwanese cohort with ALS
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2021
Kang-Yang Jih, Kon-Ping Lin, Pei-Chien Tsai, Bing-Wen Soong, Yi-Chu Liao, Yi-Chung Lee
Amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disorder affecting both upper and lower motor neurons, manifests progressive muscle atrophy, limbs weakness, bulbar palsy, and consequently leads to respiratory failure. Genetic factors play an important role in ALS pathogenesis, as demonstrated by the fact that approximately 10% of all ALS cases are familial ones (1). Currently, there are more than 30 ALS-related genes reported in the literature and more to be identified yet. Noticeably, intermediate-length CAG repeats in the ataxin 2 gene (ATXN2) have been well recognized as a risk factor for ALS. A CAG expansion in ATXN2 with more than 34 repeats results in spinocerebellar ataxia (SCA) type 2, whereas ATXN2 with an intermediate length of CAG expansion (27–33 repeats) increases the risk of ALS (2). Analogously, intermediate-length polyglutamine expansions in the ataxin 1 gene (ATXN1) have also been demonstrated to be associated with ALS (3,4). However, the role of similar trinucleotide repeat expansion in the TATA-box binding protein gene (TBP), the disease gene for SCA type 17 (SCA17), remains elusive in ALS.
Identification of key miRNA signature and pathways involved in multiple myeloma by integrated bioinformatics analysis
Published in Hematology, 2021
Xiushuai Dong, Gang Lu, Xianwei Su, Jie Liu, Xi Chen, Yaoyao Tian, Yuying Chang, Lianjie Wang, Wei Wang, Jin Zhou
Based on the PPI network, we further constructed a PPI sub-network among up-regulated and down-regulated DEMirTGs, which contained 120 up-regulated and 406 down-regulated genes, as shown in Figure 3A. Many hub genes within this network included ATXN1, APP and CRK. Furthermore, we obtained known MM-related genes from GAD database and MM prognostic genes from six published researches (see Materials and methods, Table S5). As a result, the PPI sub-network contained many MM-related genes, including IGF1R, CASP3, KRAS and prognostic genes, including PTPN1 and HMGB3. By utilizing cluster analysis of the sub-network in Cytotype MCODE, we identified one significant module based on the degree of importance, which contained five nodes and nine edges (one up-regulated and four down-regulated DEMirTGs, Figure 3(B)). This module contained hub gene, TP53, which was also known as MM-related genes and other genes within this module such as KAT2B and SIRT1 might also be associated with MM formation or prognosis. The genes (SIRT2 and SIRT3) from the same family with SIRT1 were correlated with redox imbalance and advanced clinical stage in MM patients in recent research [37]. Previous findings revealed that target strategy on SIRT1 can inhibit the proliferation of MM cells [38], and the expression level of SIRT1 was also associated with poor prognosis of diffuse large B-cell lymphoma [39].
Advances in the understanding of hereditary ataxia – implications for future patients
Published in Expert Opinion on Orphan Drugs, 2018
Anna Zeitlberger, Heather Ging, Suran Nethisinghe, Paola Giunti
The term hereditary ataxia encompasses a clinically and genetically heterogeneous group of disorders. They share a progressive incoordination of motor activity affecting gait, extraocular movements, and speech [1]. Underlying these conditions is a well-described genetic association with autosomal dominant, autosomal recessive, X-linked or mitochondrial transmission [2]. Even though marked variability in intra- and interfamilial phenotypical presentation were identified early in their description, and different genetic backgrounds suspected, the number of distinct genetic causes has only recently begun to be unraveled [3]. The first milestones of gene discovery in hereditary ataxia were made in the early 1990s with the discovery of pathogenic repetitive trinucleotide repeat (TR) expansions within the ATXN1 gene in Spinocerebellar ataxia type 1, and the FXN gene in Friedreich’s ataxia (FRDA) [4,5]. Both causative genes were discovered by linkage analysis and subsequent Sanger sequencing.