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Generation of six induced pluripotent stem cell lines from patients with amyotrophic lateral sclerosis with associated genetic mutations in either FUS or ANXA11.

ABSTRACT: Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of upper and lower motor neurons, causing gradual paralysis, and resulting in death 3-5 years from diagnosis. ALS causative mutations have been identified in multiple genes, including Fused in sarcoma (FUS), and recently characterized Annexin A11 (ANXA11). We have derived induced pluripotent stem cell (iPSC) lines from six ALS patient lymphoblastoid cell lines, three with mutations in FUS (Q519E, R521H, R522G), and three with mutations in ANXA11 (G38R, D40G, R235Q). These lines have been characterized and provide a novel resource for investigation into ALS pathology.

SUBMITTER: Hedges EC

PROVIDER: S-EPMC7988463 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Generation of six induced pluripotent stem cell lines from patients with amyotrophic lateral sclerosis with associated genetic mutations in either FUS or ANXA11.

Hedges Erin C EC Topp Simon S Shaw Christopher E CE Nishimura Agnes L AL

Stem cell research 20210212

Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of upper and lower motor neurons, causing gradual paralysis, and resulting in death 3-5 years from diagnosis. ALS causative mutations have been identified in multiple genes, including Fused in sarcoma (FUS), and recently characterized Annexin A11 (ANXA11). We have derived induced pluripotent stem cell (iPSC) lines from six ALS patient lymphoblastoid cell lines, three with mutations in FUS (Q519E, R521H, R522G), and three with m ...[more]

PMID: 33610019

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Project description:Abstract Increasing genetic evidence supports the hypothesis that variants in the annexin A11 gene (ANXA11) contribute to amyotrophic lateral sclerosis pathogenesis. Therefore, we studied the clinical aspects of sporadic amyotrophic lateral sclerosis patients carrying ANXA11 variants. We also implemented functional experiments to verify the pathogenicity of the hotspot variants associated with amyotrophic lateral sclerosis-frontotemporal dementia. Korean patients diagnosed with amyotrophic lateral sclerosis (n = 882) underwent genetic evaluations through next-generation sequencing, which identified 16 ANXA11 variants in 26 patients. We analysed their clinical features, such as the age of onset, progression rate, initial symptoms and cognitive status. To evaluate the functional significance of the ANXA11 variants in amyotrophic lateral sclerosis-frontotemporal dementia pathology, we additionally utilized patient fibroblasts carrying frontotemporal dementia-linked ANXA11 variants (p.P36R and p.D40G) to perform a series of in vitro studies, including calcium imaging, stress granule dynamics and protein translation. The frequency of the pathogenic or likely pathogenic variants of ANXA11 was 0.3% and the frequency of variants classified as variants of unknown significance was 2.6%. The patients with variants in the low-complexity domain presented unique clinical features, including late-onset, a high prevalence of amyotrophic lateral sclerosis-frontotemporal dementia, a fast initial progression rate and a high tendency for bulbar-onset compared with patients carrying variants in the C-terminal repeated annexin homology domains. In addition, functional studies using amyotrophic lateral sclerosis-frontotemporal dementia patient fibroblasts revealed that the ANXA11 variants p.P36R and p.D40G impaired intracellular calcium homeostasis, stress granule disassembly and protein translation. This study suggests that the clinical manifestations of amyotrophic lateral sclerosis and amyotrophic lateral sclerosis-frontotemporal dementia spectrum patients with ANXA11 variants could be distinctively characterized depending upon the location of the variant. This study investigated the clinical aspects of sporadic amyotrophic lateral sclerosis patients carrying ANXA11 variants and verified the pathogenicity of the hotspot variants associated with amyotrophic lateral sclerosis-frontotemporal dementia. Sung et al. reported unique clinical features of the patients with variants in the low-complexity domain with in vitro study results. Graphical Abstract Graphical abstract

Dataset Information

Generation of six induced pluripotent stem cell lines from patients with amyotrophic lateral sclerosis with associated genetic mutations in either FUS or ANXA11.

Publications

Generation of six induced pluripotent stem cell lines from patients with amyotrophic lateral sclerosis with associated genetic mutations in either FUS or ANXA11.

Similar Datasets

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