scholarly journals ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Gijs H P Tazelaar ◽  
Steven Boeynaems ◽  
Mathias De Decker ◽  
Joke J F A van Vugt ◽  
Lindy Kool ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Large Scale ◽  
Amyotrophic Lateral Sclerosis Patient ◽  
International Study ◽  
Spinocerebellar Ataxia Type ◽  
Published Data ◽  
Polyglutamine Expansions ◽  
Similar Disease ◽  
Repeat Expansions ◽  
Lateral Sclerosis

Abstract Increasingly, repeat expansions are being identified as part of the complex genetic architecture of amyotrophic lateral sclerosis. To date, several repeat expansions have been genetically associated with the disease: intronic repeat expansions in C9orf72, polyglutamine expansions in ATXN2 and polyalanine expansions in NIPA1. Together with previously published data, the identification of an amyotrophic lateral sclerosis patient with a family history of spinocerebellar ataxia type 1, caused by polyglutamine expansions in ATXN1, suggested a similar disease association for the repeat expansion in ATXN1. We, therefore, performed a large-scale international study in 11 700 individuals, in which we showed a significant association between intermediate ATXN1 repeat expansions and amyotrophic lateral sclerosis (P = 3.33 × 10−7). Subsequent functional experiments have shown that ATXN1 reduces the nucleocytoplasmic ratio of TDP-43 and enhances amyotrophic lateral sclerosis phenotypes in Drosophila, further emphasizing the role of polyglutamine repeat expansions in the pathophysiology of amyotrophic lateral sclerosis.

scholarly journals Amyotrophic Lateral Sclerosis and Spinocerebellar Ataxia Type 2 in a Family With Full CAG Repeat Expansions ofATXN2

2013 ◽  
Author(s):  
Sirinan Tazen ◽  
Karla Figueroa ◽  
Justin Y. Kwan ◽  
Jill Goldman ◽  
Ann Hunt ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Spinocerebellar Ataxia ◽  
Cag Repeat ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 2 ◽  
Repeat Expansions ◽  
Lateral Sclerosis

scholarly journals Japanese amyotrophic lateral sclerosis patient with learning disabilities with a deletion mutation in the C-terminal of theFUS/TLSgene

2015 ◽  
Vol 3 (5) ◽  
pp. 192-193 ◽  
Author(s):  
Akiko Onohara ◽  
Kishin Koh ◽  
Takamura Nagasaka ◽  
Kazumasa Shindo ◽  
Masaaki Kato ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Learning Disabilities ◽  
Amyotrophic Lateral Sclerosis Patient ◽  
Deletion Mutation ◽  
Lateral Sclerosis

A novel SOD1 mutation in a young amyotrophic lateral sclerosis patient with a very slowly progressive clinical course

2010 ◽  
Vol 42 (4) ◽  
pp. 596-597 ◽  
Author(s):  
Eleni Georgoulopoulou ◽  
Cinzia Gellera ◽  
Cinzia Bragato ◽  
Patrizia Sola ◽  
Annalisa Chiari ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Clinical Course ◽  
Amyotrophic Lateral Sclerosis Patient ◽  
Sod1 Mutation ◽  
Lateral Sclerosis

scholarly journals Amyotrophic lateral sclerosis patient iPSC-derived astrocytes impair autophagy via non-cell autonomous mechanisms

2017 ◽  
Vol 10 (1) ◽  
Author(s):  
Martin Madill ◽  
Katya McDonagh ◽  
Jun Ma ◽  
Alice Vajda ◽  
Paul McLoughlin ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Amyotrophic Lateral Sclerosis Patient ◽  
Lateral Sclerosis

scholarly journals Concomitant gain and loss of function pathomechanisms in C9ORF72 amyotrophic lateral sclerosis

2021 ◽  
Vol 4 (4) ◽  
pp. e202000764
Author(s):  
Arun Pal ◽  
Benedikt Kretner ◽  
Masin Abo-Rady ◽  
Hannes Glaβ ◽  
Banaja P Dash ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Loss Of Function ◽  
Dna Double Strand Breaks ◽  
Hexanucleotide Repeat ◽  
Rna Foci ◽  
Repeat Expansions ◽  
Organelle Motility ◽  
Trafficking Defects ◽  
Induced Pluripotent ◽  
Lateral Sclerosis

Intronic hexanucleotide repeat expansions (HREs) in C9ORF72 are the most frequent genetic cause of amyotrophic lateral sclerosis, a devastating, incurable motoneuron (MN) disease. The mechanism by which HREs trigger pathogenesis remains elusive. The discovery of repeat-associated non-ATG (RAN) translation of dipeptide repeat proteins (DPRs) from HREs along with reduced exonic C9ORF72 expression suggests gain of toxic functions (GOFs) through DPRs versus loss of C9ORF72 functions (LOFs). Through multiparametric high-content (HC) live profiling in spinal MNs from induced pluripotent stem cells and comparison to mutant FUS and TDP43, we show that HRE C9ORF72 caused a distinct, later spatiotemporal appearance of mainly proximal axonal organelle motility deficits concomitant to augmented DNA double-strand breaks (DSBs), RNA foci, DPRs, and apoptosis. We show that both GOFs and LOFs were necessary to yield the overall C9ORF72 pathology. Increased RNA foci and DPRs concurred with onset of axon trafficking defects, DSBs, and cell death, although DSB induction itself did not phenocopy C9ORF72 mutants. Interestingly, the majority of LOF-specific DEGs were shared with HRE-mediated GOF DEGs. Finally, C9ORF72 LOF was sufficient—albeit to a smaller extent—to induce premature distal axonal trafficking deficits and increased DSBs.

scholarly journals A Natural History Comparison of SOD1-Mutant Patients with Amyotrophic Lateral Sclerosis between Chinese and German Populations

2021 ◽  
Author(s):  
Lu Tang ◽  
Johannes Dorst ◽  
Lu Chen ◽  
Xiaolu Liu ◽  
Yan Ma ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Large Scale ◽  
Age Of Onset ◽  
Diagnostic Delay ◽  
Chinese Patients ◽  
Common Mutation ◽  
Progression Rate ◽  
Causative Gene ◽  
Sod1 Mutant ◽  
Lateral Sclerosis

Abstract Background: The gene coding the Cu/Zn superoxide dismutase ( SOD1 ) was the first-identified causative gene of amyotrophic lateral sclerosis (ALS), and the second most common genetic cause for ALS worldwide. The promising therapeutic approaches targeting SOD1 mutations are on the road. The purpose of the present study was to compare the mutational and clinical features of Chinese and German patients with ALS carrying mutations in SOD1 gene, which will facilitate the strategy and design of SOD1 -targeted trials.Methods: Demographic and clinical characteristics were collected from two longitudinal cohorts in China and Germany. Chinese and German patients carrying SOD1 mutations were compared with regard to mutational distribution, age of onset, site of onset, body mass index (BMI) at diagnosis, diagnostic delay, progression rate, and survival.Results: A total of 66 Chinese and 84 German patients with 69 distinct SOD1 mutations were identified. The most common mutation in both populations was p.His47Arg. It was found in 8 Chinese and 2 German patients and consistently showed a slow progression of disease in both countries. Across all mutations, Chinese patients showed a younger age of onset (43.9 vs 49.9 years, p=0.002), a higher proportion of young-onset cases (62.5% vs 30.7%, p<0.001) and a lower BMI at diagnosis (22.8 vs 26.0, p<0.001) compared to German patients. Although riluzole intake was less frequent in Chinese patients (28.3% vs 81.3%, p<0.001), no difference in survival between populations was observed (p=0.90). Across both cohorts, female patients had a longer diagnostic delay (15.0 vs 11.0 months, p=0.01) and a prolonged survival (248.0 vs 60.0 months, p=0.005) compared to male patients.Conclusions: Our data demonstrate the distinct mutational and clinical spectrums of SOD1 -mutant patients in Asian and European populations. Clinical phenotypes seem to be primarily influenced by mutation-specific, albeit not excluding ethnicity-specific factors. Further large-scale transethnical studies are needed to clarify determinants and modifiers of SOD1 phenotypes.

scholarly journals Genomic Portrait of a Sporadic Amyotrophic Lateral Sclerosis Case in a Large Spinocerebellar Ataxia Type 1 Family

2020 ◽  
Vol 10 (4) ◽  
pp. 262
Author(s):  
Giovanna Morello ◽  
Giulia Gentile ◽  
Rossella Spataro ◽  
Antonio Gianmaria Spampinato ◽  
Maria Guarnaccia ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Spinocerebellar Ataxia ◽  
Complex Disease ◽  
Spinocerebellar Ataxia Type ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Spinocerebellar Ataxia Type 1 ◽  
Pathogenic Variants ◽  
Lateral Sclerosis

Background: Repeat expansions in the spinocerebellar ataxia type 1 (SCA1) gene ATXN1 increases the risk for amyotrophic lateral sclerosis (ALS), supporting a relationship between these disorders. We recently reported the co-existence, in a large SCA1 family, of a clinically definite ALS individual bearing an intermediate ATXN1 expansion and SCA1 patients with a full expansion, some of which manifested signs of lower motor neuron involvement. Methods: In this study, we employed a systems biology approach that integrated multiple genomic analyses of the ALS patient and some SCA1 family members. Results: Our analysis identified common and distinctive candidate genes/variants and related biological processes that, in addition to or in combination with ATXN1, may contribute to motor neuron degeneration phenotype. Among these, we distinguished ALS-specific likely pathogenic variants in TAF15 and C9ORF72, two ALS-linked genes involved in the regulation of RNA metabolism, similarly to ATXN1, suggesting a selective role for this pathway in ALS pathogenesis. Conclusions: Overall, our work supports the utility to apply personal genomic information for characterizing complex disease phenotypes.

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