Genetic analysis of ANXA11 variants in a Han Chinese cohort with amyotrophic lateral sclerosis in Taiwan

Tsai, Pei‐Chien; Liao, Yi‐Chu; Jih, Kang-Yang; Soong, Bing Wen; Lin, Kon‐Ping; Lee, Yi‐Chung

doi:10.1016/j.neurobiolaging.2018.07.002

Cited by 13 publications

(12 citation statements)

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“…Mutations in ANXA11 cause ALS and a related neurodegenerative disorder, frontotemporal dementia (FTD). Numerous mutations in ANXA11 have now been described by several different groups, and may account for up to 6% of familial ALS in Chinese populations (Smith et al, 2017;Tsai et al, 2018;Zhang et al, 2018a). Pathogenic mutations occur in both the N-terminal low complexity region and the C-terminal membrane binding region.…”

Section: Discussionmentioning

confidence: 99%

“…Of these, annexin A11 (ANXA11) was the highest-ranked lysosome-interacting protein based on LAMP1-APEX2 proteomics. Mutations in ANXA11 are associated with ALS, a neurodegenerative disease in which dysfunction of lysosomal and RNA granule biology play causal roles (Smith et al, 2017;Tsai et al, 2018;Zhang et al, 2018a). We performed structural modeling of ANXA11 as a first step in its characterization ( Figure 2G).…”

Section: (Legend Continued On Next Page)mentioning

confidence: 99%

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RNA Granules Hitchhike on Lysosomes for Long-Distance Transport, Using Annexin A11 as a Molecular Tether

Liao

Fernandopulle

Wang

et al. 2019

Cell

381

412

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Section: Discussionmentioning

confidence: 99%

Section: (Legend Continued On Next Page)mentioning

confidence: 99%

RNA Granules Hitchhike on Lysosomes for Long-Distance Transport, Using Annexin A11 as a Molecular Tether

Liao

Fernandopulle

Wang

et al. 2019

Cell

381

412

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“…Mutations in ANXA11 were recently identified in patients with familial and sporadic ALS by whole-exome sequencing (13)(14)(15)(16). ANXA11 is a member of the Ca 2+ -dependent phospholipid-binding protein family, which comprises an extended N-terminal domain containing a binding site for another Ca 2+ -binding protein (CBP), calcyclin, and C-terminal repeated annexin (ANX) homology domains p.D40G; 0, 0.00005629, and 0.00007705 for p.G38R; 0, 0.0003659, and 0 for p.G137R; 0, 0.0003267, and 0.00000775 for p.R456H in East Asian, South Asian, and European populations, respectively).…”

Section: Introductionmentioning

confidence: 99%

ANXA11 mutations in ALS cause dysregulation of calcium homeostasis and stress granule dynamics

et al. 2020

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Dysregulation of calcium ion homeostasis and abnormal protein aggregation have been proposed as major pathogenic hallmarks underpinning selective degeneration of motor neurons in amyotrophic lateral sclerosis (ALS). Recently, mutations in annexin A11 (ANXA11), a gene encoding a Ca2+-dependent phospholipid-binding protein, have been identified in familial and sporadic ALS. However, the physiological and pathophysiological roles of ANXA11 remain unknown. Here, we report functions of ANXA11 related to intracellular Ca2+ homeostasis and stress granule dynamics. We analyzed the exome sequences of 500 Korean patients with sALS and identified nine ANXA11 variants in 13 patients. The amino-terminal variants p.G38R and p.D40G within the low-complexity domain of ANXA11 enhanced aggregation propensity, whereas the carboxyl-terminal ANX domain variants p.H390P and p.R456H altered Ca2+ responses. Furthermore, all four variants in ANXA11 underwent abnormal phase separation to form droplets with aggregates and led to the alteration of the biophysical properties of ANXA11. These functional defects caused by ALS-linked variants induced alterations in both intracellular Ca2+ homeostasis and stress granule disassembly. We also revealed that p.G228Lfs*29 reduced ANXA11 expression and impaired Ca2+ homeostasis, as caused by missense variants. Ca2+-dependent interaction and coaggregation between ANXA11 and ALS-causative RNA-binding proteins, FUS and hnRNPA1, were observed in motor neuron cells and brain from a patient with ALS-FUS. The expression of ALS-linked ANXA11 variants in motor neuron cells caused cytoplasmic sequestration of endogenous FUS and triggered neuronal apoptosis. Together, our findings suggest that disease-associated ANXA11 mutations can contribute to ALS pathogenesis through toxic gain-of-function mechanisms involving abnormal protein aggregation.

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“…Mutations in ANXA11 are associated with ALS, a neurodegenerative disease in which dysfunction of lysosomal and RNA granule biology play causal roles (Smith et al, 2017;Tsai et al, 2018;Zhang et al, 2018a). We performed structural modeling of ANXA11 as a first step in its characterization (Figure 2G).…”

Section: Identification Of Anxa11 As a Mediator Of Rna Granule-lysosome Associationsmentioning

confidence: 99%

Cellular Hitchhiking—a New Way to Understand ALS Pathways—and Perhaps Provide a Potential Target to Stop It

Robinson¹

2019

Neurology Today

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Genetic analysis of ANXA11 variants in a Han Chinese cohort with amyotrophic lateral sclerosis in Taiwan

Cited by 13 publications

References 0 publications

RNA Granules Hitchhike on Lysosomes for Long-Distance Transport, Using Annexin A11 as a Molecular Tether

RNA Granules Hitchhike on Lysosomes for Long-Distance Transport, Using Annexin A11 as a Molecular Tether

ANXA11 mutations in ALS cause dysregulation of calcium homeostasis and stress granule dynamics

Cellular Hitchhiking—a New Way to Understand ALS Pathways—and Perhaps Provide a Potential Target to Stop It

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