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IntroductionVariants of uncertain significance (VUS) surged with affordable genetic testing, posing challenges for determining pathogenicity. We examine the pathogenicity of a novel VUS P93S in Annexin A11 (ANXA11) - an amyotrophic lateral sclerosis/frontotemporal dementia-associated gene - in a corticobasal syndrome kindred. Established ANXA11 mutations cause ANXA11 aggregation, altered lysosomal-RNA granule co-trafficking, and transactive response DNA binding protein of 43 kDa (TDP-43) mis-localization.MethodsWe described the clinical presentation and explored the phenotypic diversity of ANXA11 variants. P93S's effect on ANXA11 function and TDP-43 biology was characterized in induced pluripotent stem cell-derived neurons alongside multiomic neuronal and microglial profiling.ResultsANXA11 mutations were linked to corticobasal syndrome cases. P93S led to decreased lysosome colocalization, neuritic RNA, and nuclear TDP-43 with cryptic exon expression. Multiomic microglial signatures implicated immune dysregulation and interferon signaling pathways.DiscussionThis study establishes ANXA11 P93S pathogenicity, broadens the phenotypic spectrum of ANXA11 mutations, underscores neuronal and microglial dysfunction in ANXA11 pathophysiology, and demonstrates the potential of cellular models to determine variant pathogenicity.HighlightsANXA11 P93S is a pathogenic variant. Corticobasal syndrome is part of the ANXA11 phenotypic spectrum. Hybridization chain reaction fluorescence in situ hybridization (HCR FISH) is a new tool for the detection of cryptic exons due to TDP-43-related loss of splicing regulation. Microglial ANXA11 and related immune pathways are important drivers of disease. Cellular models are powerful tools for adjudicating variants of uncertain significance.

Mutations in the ANXA11 gene, encoding an RNA-binding protein, have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), but the underlying in vivo mechanisms remain unclear. This study examines the clinical features of ALS patients harboring the ANXA11 hotspot mutation p.P36R, characterized by late-onset motor neuron disease and occasional multi-system involvement. To elucidate the pathogenesis, we developed a knock-in mouse model carrying the p.P36R mutation. In both heterozygous and homozygous mutant mice, ANXA11 protein levels were comparable to those in wild-type. Both groups exhibited late-onset motor dysfunction at approximately 10 months of age, with similar survival rates to wild-type (> 24 months) and no signs of dementia. Pathological analysis revealed early abnormal aggregates in spinal cord motor neurons, cortical neurons, and muscle cells of homozygous mice. From 2 months of age, we observed mislocalized ANXA11 aggregates, SQSTM1/p62-positive inclusions, and cytoplasmic TDP-43 mislocalization, which intensified with disease progression. Importantly, mutant ANXA11 co-aggregated with TDP-43 and SQSTM1/p62-positive inclusions. Electron microscopy of the gastrocnemius muscle uncovered myofibrillar abnormalities, including sarcomeric disorganization, Z-disc dissolution, and subsarcolemmal electron-dense structures within autophagic vacuoles. Autophagic flux, initially intact at 2 months, was impaired by 9 months, as evidenced by decreased Beclin-1 and LC3BII/I levels and increased SQSTM1/p62 expression, coinciding with mTORC1 hyperactivation. Significant motor neuron loss and neuroinflammation were detected by 9 months, with marked muscle dystrophy apparent by 12 months compared to wild-type controls. These findings implicate the gain-of-function ANXA11 mutation drives late-onset motor neuron disease by early presymptomatic proteinopathy, progressive neuronal degeneration, neuroinflammation, and autophagic dysfunction. [ABSTRACT FROM AUTHOR]

The sensitivity of laryngeal squamous cell carcinoma (LSCC) to chemotherapy shows large heterogeneity. The role of miRNA in small extracellular vesicles (sEV) in chemotherapy resistance is under investigation. However, the regulation and sorting mechanism of sEV miRNAs remains unclear. In this study, small RNA sequencing was used to explore miRNA expression profiles in sEV of LSCC after cisplatin stimulation; RNA pull‐down, mass spectrometry, and EMSA were used to clarify the binding of candidate RNA‐binding protein (RBP) and candidate miRNA. Immunostaining and microRNA fluorescence in situ hybridization were performed to identify how candidate RBP affects miRNA stability and nuclear/cytoplasmic distribution. In vivo experiments were performed to verify the biological functions and response to cisplatin of candidate RBP. We found that cisplatin stimulation induced increased expression of miR‐148a‐3p and sEV sorting. ANXA11 binds to miR‐148a‐3p in a sequence‐specific manner. ANXA11 inhibits tumor cell proliferation and drug resistance by binding to and retaining miR‐148a‐3p. Cisplatin stimulation reduced ANXA11 expression and promoted miR‐148a‐3p efflux through sEV pathways. ANXA11 overexpression reduced in vivo tumor proliferation and cisplatin‐resistance. Taken together, ANXA11 mediates cisplatin resistance through sEV miRNA resorting. Mechanically, ANXA11 binds to miR‐148a‐3p in a sequence‐specific manner to regulate its resorting and thus influences tumor proliferation and chemoresistance. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) can function as functional molecules in hepatocellular carcinoma (HCC). Herein, circRNA superoxide dismutase 2 (circSOD2) was researched in HCC progression and immune system. The real-time polymerase chain reaction (qRT-PCR) was used for quantification of circSOD2, microRNA-497-5p (miR-497-5p) and Annexin A11 (ANXA11). Cell assays were performed by 3-(4, 5-dimethylthiazol-2-y1)-2, 5-diphenyl tetrazolium bromide (MTT) and colony formation assays for proliferation, flow cytometry for apoptosis and cell cycle, wound healing assay for migration and transwell assay for migration/invasion. ANXA11 and metastatic protein levels were measured by western blot. Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were performed to analyze target binding. CD8+ T cell immunity was assessed by Immunohistochemistry (IHC) assay, and the effect of circSOD2 on programmed cell death 1 (PD-1) immune checkpoint inhibitors (anti-PD-1) therapy was evaluated by mice xenograft assay. CircSOD2 was upregulated in HCC tissues and cells. Knockdown of circSOD2 resulted in HCC cell growth inhibition, apoptosis promotion, cell cycle arrest and metastasis suppression. Mechanically, circSOD2 promoted HCC development by acting as a miR-497-5p sponge and miR-497-5p played a tumor-inhibitory role in HCC cells by targeting ANXA11. Moreover, circSOD2 induced upregulation of ANXA11 expression by interacting with miR-497-5p. Also, the promoting effects of circSOD2 on immune evasion and anti-PD-1 resistance were related to miR-497-5p/ANXA11 axis. This study elucidated the pivotal function of circSOD2 in HCC progression and immunosuppression by mediating miR-497-6p/ANXA11 axis. CircSOD2/miR-497-5p/ANXA11 axis was a novel view of circRNA research in HCC. [ABSTRACT FROM AUTHOR]

BackgroundANXA11 mutations were first reported to be associated with amyotrophic lateral sclerosis (ALS) in 2017. Several studies have investigated the prevalence of ANXA11 mutations in different populations, while less is known about the spectrum of phenotypes and the genotype–phenotype correlation with this gene mutation.Case presentationHere, we report a 74-year-old man who was initially diagnosed with progressive supranuclear palsy (PSP) because of repeated falls, slight upward gaze palsy, and mild cognitive dysfunction at the onset. He finally turned out to be ALS with more and more prominent limb weakness and atrophy, together with the evidence of chronic neurogenic change and ongoing denervation on electromyography. Brain magnetic resonance imaging showed extensive cortical atrophy. A missense mutation c.119A > G (p.D40G) on the ANXA11 gene was identified using whole-exome sequencing, which confirmed the diagnosis of ALS. We performed a systematic review of the literature about ALS-relevant cases with ANXA11 mutations and identified 68 affected subjects and 29 variants with the ANXA11 gene. We summarized the phenotypes of ANXA11 mutations and the clinical characteristics of nine patients harboring the ANXA11 p.D40G variant including our case.ConclusionsThe phenotype of ANXA11-related cases is heterogeneous, and most cases showed typical ALS, while some could also have the characteristics of frontotemporal dementia (FTD) and PSP, even inclusion body myopathies (hIBM) occurred in familial ALS (FALS). Our patient presented with ALS with a co-morbid PSP-like symptom (ALS-PSP) phenotype, which has not been reported. Except for our patient, the remaining eight patients with the ANXA11 p.D40G variant presented with a classical ALS phenotype without cognitive impairment.

Background: The Annexin A11 (ANXA11) gene has been newly identified as a causative gene of amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia (FTD). The current study aimed to investigate the ANXA11 mutations in a Chinese ALS-FTD or FTD cohort. Methods: We included ten probands/patients with suspected ALS-FTD or FTD. Mutational analysis of ANXA11 was performed through Next Generation Sequencing (NGS) and Sanger sequencing. We collected and reviewed clinical presentation, neuropsychology test results, brain-imaging findings, and electrophysiological examination findings. Results: In total, six probands presented with ALS-FTD, and four with behavior variant FTD(bv-FTD). We identified a non-synonymous heterozygousmutation (c.119A>G, p.D40G) of ANXA11 in proband 1, which is associated with ALS. However, this is the first report of the mutation causing ALS-FTD. Proband 1 started with abnormal behavior and progressed to classic uppermotor nervous disease. Magnetic resonance imaging (MRI) showed significant bilateral temporal lobe atrophy and bilateral hyperintensities along the corticospinal tracts.18F-AV45-PET imaging showed negative amyloid deposits. Conclusion: ANXA11-related diseases have high clinical and genetic heterogeneity. Our study confirmed the contribution of ANXA11 mutations to ALS-FTD. The ANXA11 mutations established a complex genotype-phenotype correlation in ALS-FTD.Our research further elucidated the genetic mechanism of ALS-FTD and contributed to setting the foundation of future targeted therapy. [ABSTRACT FROM AUTHOR]

Sarcoidosis is an immune mediated granulomatous disease commonly affecting the lungs. Genome wide association studies identified many genomic regions that are shared among multiple immune mediated diseases. However, ANXA11 gene polymorphism rs1049550 is exclusively associated with sarcoidosis, making it a key gene of interest for sarcoidosis disease pathogenesis. However, sarcoidosis is a heterogeneous disease and contradictory findings for ANXA11 have been reported for disease phenotypes. We performed a case–control association study to investigate if ANXA11 associates with benign (Löfgren's syndrome (LS)) or chronic sarcoidosis and performed a meta-analysis on previously reported findings. A total of 262 sarcoidosis patients, of which 149 had LS and 113 chronic sarcoidosis, and 363 controls were genotyped for rs1049550. Meta-analysis included allele findings for rs1049550 from 6 additional studies. We found a significantly lower T allele frequency in sarcoidosis patients than in healthy controls (0.30 vs. 0.41, respectively, odds ratio (OR) 0.61, 95% confidence interval (CI) 0.48–0.77, p = 3 × 10−5). In LS the T allele frequency of 0.33, and in chronic sarcoidosis the T allele frequency of 0.26 were significantly lower than in healthy controls (OR 0.69, 95% CI 0.52–0.92, p = 0.01 and OR 0.51, 95% CI 0.36–0.70, p = 4 × 10−5, respectively). Meta-analysis including previously published European, African American and Asian cohorts confirmed the association of rs1049550 with sarcoidosis and resulted in a pooled OR of 0.70 (CI 0.66–0.75, p = 3.58 × 10−29). Presence of the T allele of rs1049550 in ANXA11 is protective for sarcoidosis, including benign and chronic phenotypes of the disease. [ABSTRACT FROM AUTHOR]

Abstract Background Glioma is one prevalent malignant tumor originates from the central nervous system. Dysregulation of long non-coding RNAs (lncRNAs) has been found to be a molecular signature behind the pathology of a variety of cancers, including glioma. EIF3J antisense RNA 1 (EIF3J-AS1) is a novel lncRNA, whose performance in carcinogenesis has been unfolded. Nevertheless, the role of EIF3J-AS1 has never been investigated in glioma. Methods qRT-PCR analysis was adopted to evaluate the relative levels of RNAs. In vitro functional assays, including colony formation, EdU, TUNEL and caspase-3/8/9 activity assays were conducted to study the impacts of EIF3J-AS1 on glioma. Dual-luciferase activity assays, RNA pull down assay and RIP assay were performed to elucidate molecular interplay among genes. Results EIF3J-AS1 was overexpressed in glioma cell lines. Knockdown of EIF3J-AS1 hampered glioma malignant phenotypes. MiR-1343-3p could bind to EIF3J-AS1. Moreover, miR-1343-3p targeted Annexin A11 (ANXA11) in its 3′UTR region. Mechanistically, EIF3J-AS1 relieved ANXA11 from miR-1343-3p silencing in the EIF3J-AS1/miR-1343-3p/ANXA11 RNA induced silencing complex (RISC), thus eliciting promoting effects on glioma progression. MiR-1343-3p inhibitor and ANXA11 overexpression offset the inhibitory impacts of EIF3J-AS1 silencing on glioma development. Conclusion EIF3J-AS1/miR-1343-3p/ANXA11 axis significantly affected biological behaviors in glioma, suggesting new therapeutic target for glioma treatment.

We report a patient with right‐predominant semantic variant primary progressive aphsia linked with p.Asp40Gly variant of ANXA11, which is the first description of frontotemporal dementia without clinical and electrophysiological evidences of amyotrophic lateral sclerosis associated with a known pathogenic variant of ANXA11. [ABSTRACT FROM AUTHOR]

Abstract Background Accumulating evidence has highlighted the potential role of long non-coding RNAs (lncRNAs) in the biological behaviors of hepatocellular carcinoma (HCC). Here, we elucidated the function and possible molecular mechanisms of the effect of lncRNA-AGAP2-AS1 on the biological behaviors of HCC. Methods EdU, Transwell and flow cytometry were used to determine proliferation, migration, invasion and apoptosis of HCC cells in vitro. The subcutaneous tumor model and lung metastasis mouse model in nude mice was established to detect tumor growth and metastasis of HCC in vivo. The direct binding of miR-16-5p to 3’UTR of ANXA11 was confirmed by luciferase reporter assay. The expression of AGAP2-AS1 and miR-16-5p in HCC specimens and cell lines were detected by real-time PCR. The correlation among AGAP2-AS1 and miR-16-5p were disclosed by a dual-luciferase reporter assay, RIP assay and biotin pull-down assay. Results Here, we demonstrated that AGAP2-AS1 expression was up-regulated in HCC tissues and cell lines, especially in metastatic and recurrent cases. Gain- and loss-of-function experiments indicated that AGAP2-AS1 promoted cell proliferation, migration, invasion, EMT progression and inhibited apoptosis of HCC cells in vitro and in vivo. Further studies demonstrated that AGAP2-AS1 could function as a competing endogenous RNA (ceRNA) by sponging miR-16-5p in HCC cells. Functionally, gain- and loss-of-function studies showed that miR-16-5p promoted HCC progression and alteration of miR-16-5p abolished the promotive effects of AGAP2-AS1 on HCC cells. Moreover, ANXA11 was identified as direct downstream targets of miR-16-5p in HCC cells, and mediated the functional effects of miR-16-5p and AGAP2-AS1 in HCC, resulting in AKT signaling activation. Clinically, AGAP2-AS1 and miR-16-5p expression were markedly correlated with adverse clinical features and poor prognosis of HCC patients. We showed that hypoxia was responsible for the overexpression of AGAP2-AS1 in HCC. And the promoting effects of hypoxia on metastasis and EMT of HCC cells were reversed by AGAP2-AS1 knockdown. Conclusions Taken together, this research supports the first evidence that AGAP2-AS1 plays an oncogenic role in HCC via AGAP2-AS1/miR-16-5p/ANXA11/AKT axis pathway and represents a promising therapeutic strategy for HCC patients.

As genetic testing has become more accessible and affordable, variants of uncertain significance (VUS) are increasingly identified, and determining whether these variants play causal roles in disease is a major challenge. The known disease-associated Annexin A11 (ANXA11) mutations result in ANXA11 aggregation, alterations in lysosomal-RNA granule co-trafficking, and TDP-43 mis-localization and present as amyotrophic lateral sclerosis or frontotemporal dementia. We identified a novel VUS in ANXA11 (P93S) in a kindred with corticobasal syndrome and unique radiographic features that segregated with disease. We then queried neurodegenerative disorder clinic databases to identify the phenotypic spread of ANXA11 mutations. Multi-modal computational analysis of this variant was performed and the effect of this VUS on ANXA11 function and TDP-43 biology was characterized in iPSC-derived neurons. Single-cell sequencing and proteomic analysis of iPSC-derived neurons and microglia were used to determine the multiomic signature of this VUS. Mutations in ANXA11 were found in association with clinically diagnosed corticobasal syndrome, thereby establishing corticobasal syndrome as part of ANXA11 clinical spectrum. In iPSC-derived neurons expressing mutant ANXA11, we found decreased colocalization of lysosomes and decreased neuritic RNA as well as decreased nuclear TDP-43 and increased formation of cryptic exons compared to controls. Multiomic assessment of the P93S variant in iPSC-derived neurons and microglia indicates that the pathogenic omic signature in neurons is modest compared to microglia. Additionally, omic studies reveal that immune dysregulation and interferon signaling pathways in microglia are central to disease. Collectively, these findings identify a new pathogenic variant in ANXA11, expand the range of clinical syndromes caused by ANXA11 mutations, and implicate both neuronal and microglia dysfunction in ANXA11 pathophysiology. This work illustrates the potential for iPSC-derived cellular models to revolutionize the variant annotation process and provides a generalizable approach to determining causality of novel variants across genes., Competing Interests: Competing interests JSY serves on the scientific advisory board for the Epstein Family Alzheimer’s Research Collaboration. DSM is an advisor for Dyno Therapeutics, Octant, Jura Bio, Tectonic Therapeutic, and Genentech, and is a co-founder of Seismic Therapeutic. The authors AS, VHR, JH, SL, DMR, YAQ, KJ, XR, NLJ, AWK, MD, LVV, JNC, CT, BB, JYK, MRC, and MEW report no competing interests.

Purpose: Bevacizumab improves survival in patients with metastatic colorectal cancer (mCRC) under chemotherapy, but few predictive markers have been identified. Methods: To investigate chemosensitive single nucleotide polymorphisms (SNPs) of mCRC, we performed exome sequencing and RNA sequencing in 19 patients. A clinical association analysis was performed with the other 116 patients who had received chemotherapy to bevacizumab regimens. In vivo biodistribution studies and [F]FDG-PET imaging were performed on mice bearing human colorectal cancer (HCT116 and SW480) xenografts after injection of bevacizumab with 5-FU, leucovorin, and irinotecan (FOLFIRI). Results: PPP1R15A rs557806 showed the most significant association with FRB-driven tumor IR in exome sequencing and the highest correlation ( r = 0.74) with drug responses in RNA sequencing. Patients homozygous for the reference alleles ( GG) of PPP1R15A rs557806 exhibited greater disease control rate and a tendency toward greater objective response rate (ORR) than those with homozygous or heterozygous substitution alleles ( GC and CC; P = 0.027 and 0.073, respectively). In xenografted mice, HCT116 clones transfected with the G allele at PPP1R15A rs557806 were more sensitive to bevacizumab regimens than those with the C allele. Tumor volume of xenografts with the G allele was significantly lower than that of xenografts with the C allele ( P = 0.004, day 13). [F]FDG uptake decreased to 75 % in HCT116 xenograft-bearing mice with the G allele, whereas [F]FDG uptake was 42 % in mice xenografts with the C allele ( P = 0.032). ANXA11 rs1049550, a predictive biomarker of SNP described in our previous study, was validated using the xenograft model. Tumor volume and [F]FDG uptake analyses showed that tumors in the SW480 xenografts expressing the substitution allele ( T) at ANXA11 rs1049550 were more susceptible to FOLFIRI plus bevacizumab-induced suppression than those expressing the reference allele ( C) ( P = 0.001 and 0.026, respectively). Conclusion: ANXA11 rs1049550 and PPP1R15A rs557806 may improve the identification of mCRC patients sensitive to bevacizumab regimens, and further validation is required in large cohorts. [ABSTRACT FROM AUTHOR]

Annexin A11 (Anxa11), a Ca 2+ -regulated phospholipid-binding protein, is involved in cell apoptosis, differentiation, vesicle trafficking, cancer progression and autoimmune diseases. Previous study from our group indicated that Anxa11 was associated with lymphatic metastatic potential of murine hepatocarcinoma cells. Herein, we investigated the effects and action mechanism of Anxa11 knockdown on in vitro cell proliferation and apoptosis of Hca-F, a murine hepatocarcinoma cell with ∼ 75% lymph node metastatic potential. Real-time PCR and western blotting assays indicated that Anxa11 was significantly downregulated in monoclonal Anxa11-shRNA-transfected Hca-F cells. Anxa11 knockdown in Hca-F suppressed its in vitro proliferation and cell apoptosis capacities. Following Anxa11 knockdown in Hca-F cells, Bax/Bcl-2 expression level ratio, Akt2 and FoxO1 (pSer319) expression levels as well as MMP-9 mRNA and active MMP-9 protein levels were significantly elevated in Hca-F cells. In conclusion, Annexin A11 knockdown inhibits the in vitro proliferation and cell apoptosis of Hca-F cell via Akt2/FoxO1 and/or MMP-9 expression pathway. Anxa11 might play an important role in hepatocarcinoma cell invasion and metastasis and hepatocarcinoma malignancy. [ABSTRACT FROM AUTHOR]

Abstract: Ubiquitously expressed in many cell types, annexin A11 (Anxa11) is a member of the multigene family of Ca2+-regulated phospholipid-dependent and membrane-binding annexin proteins. Studies have shown that Anxa11 plays an important role in cell division, Ca2+ signaling, vesicle trafficking and apoptosis. The deregulation and mutation of Anxa11 are involved in systemic autoimmune diseases, sarcoidosis and the development, chemoresistance and recurrence of cancers. Malfunction of Anxa11 may lead to or enhance the metastasis, invasion and drug resistance of cancers through the platelet-derived growth factor receptor (PDGFR) pathway and/or the mitogen-activated protein kinase (MAPK)/p53 pathway. In a variety of diseases, Anxa11 is most commonly reported to function through interactions with apoptosis-linked gene-2 protein (ALG-2) and/or calcyclin (S100A6). Although it has been little studied, Anxa11 is a promising biomarker for the diagnosis, treatment and prognosis of certain diseases. In this review, the associations of Anxa11 with Ca2+-regulated exocytosis, cytokinesis, sex differentiation, autoimmune diseases, thrombolysis and cancers are summarized and interpreted. [Copyright &y& Elsevier]

A recent genome-wide association study detected a protective effect for the annexin A11 rs1049550*T allele ( R230Cvariant) in susceptibility to sarcoidosis. We evaluated the association between rs1049550 C/T and sarcoidosis susceptibility, distinct disease phenotypes and evolution in a Portuguese population. We performed a case-control study of 208 patients and 197 healthy controls. Samples were genotyped for rs1049550 C/T using real-time polymerase chain reaction. The frequency of the annexin A11 rs1049550*T allele was significantly lower in patients than in controls (33.2 vs 44.9%, P < 0.001). Odds ratio of 0.52 and 0.44 were obtained, respectively for carriers of one ( CT) and two ( TT) copies normalized to the CC wild-type genotype ( P < 0.001). There were no significant differences in patients with and without Löfgren syndrome. A significant increase in the frequency of the T allele was observed in patients with bronchoalveolar lavage (BAL) fluid neutrophilia ( P = 0.04). No significant associations were seen for lung function pattern, radiological stages or different forms of disease evolution. Our study confirms that rs1049550*T allele exerts a significant protective effect on sarcoidosis susceptibility. Given the role of annexin A11 in cell division, apoptosis and neutrophil function, this polymorphism may affect key elements of granulomatous and interstitial inflammation in sarcoidosis. [ABSTRACT FROM AUTHOR]

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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Neurofibromatosis type 1 (NF1) is a kind of common neurogenetic disorder associated with various developmental deficits. Circular RNAs (circRNAs) have been frequently verified to be crucial modulators in human diseases. However, the functions of circRNAs on the occurrence of NF1 remain largely obscure. In our study, RT-qPCR was applied to analyze circ_0061,587 expression and we noticed that circ_0061,587 expression was overtly elevated in human NF1-associated malignant peripheral nerve sheath tumor (MPNST) cell lines. Meanwhile, the results of loss-of-function assays revealed that silencing of circ_0061,587 hampered the proliferation, migration, and invasion but stimulated the apoptosis of human NF1-associated MPNST cells. In addition, mechanism assays were implemented to unveil the possible regulatory mechanism behind circ_0061,587. As a result, circ_0061,587 sequestered microRNA-485–5p (miR-485–5p) to modulate the expression of RUNX family transcription factor 1 (RUNX1) and annexin A11 (ANXA11). Finally, rescue experiments confirmed that circ_0061,587 boosted the malignant behaviors of human NF1-associated MPNST cells through up-regulating RUNX1 and ANXA11. In conclusion, circ_0061,587 functioned as an oncogene in NF1-associated MPNST cells and this study might provide novel insights for the diagnosis and treatment of NF1. • The characterization of circ_0061,587. • Silencing of circ_0061587 abrogates the proliferation, migration and invasion of ST88-14 and T-265p21 cells. • RUNX1 is positively regulated by circ_0061,587. • Circ_0061,587 sequesters miR-485–5p to modulate RUNX1 expression. • ANXA11 is also a target gene of miR-485–5p. [ABSTRACT FROM AUTHOR]

ANXA11 mutations have previously been discovered in amyotrophic lateral sclerosis (ALS) motor neuron disease. To confirm the contribution of ANXA11 mutations to ALS, a large exome data set obtained from 330 French patients, including 150 familial ALS index cases and 180 sporadic ALS cases, was analyzed, leading to the identification of 3 rare ANXA11 variants in 5 patients. The novel p.L254V variant was associated with early onset sporadic ALS. The novel p.D40Y mutation and the p.G38R variant concerned patients with predominant pyramidal tract involvement and cognitive decline. Neuropathologic findings in a p.G38R carrier associated the presence of ALS typical inclusions within the spinal cord, massive degeneration of the lateral tracts, and type A frontotemporal lobar degeneration. This mutant form of annexin A11 accumulated in various brain regions and in spinal cord motor neurons, although its stability was decreased in patients' lymphoblasts. Because most ANXA11 inclusions were not colocalized with transactive response DNA-binding protein 43 or p62 deposits, ANXA11 aggregation does not seem mandatory to trigger neurodegeneration with additional participants/partner proteins that could intervene. • Novel ANXA11 mutations are responsible for ALS. • ANXA11 mutations can be associated with early onset ALS and FTD. • Mutant G38 R ANXA11 is unstable in patient lymphoblasts. • Mutant G38 R ANXA11 led to cytoplasmic inclusions in post-mortem tissue. [ABSTRACT FROM AUTHOR]

Background: Glioma is one prevalent malignant tumor originates from the central nervous system. Dysregulation of long non-coding RNAs (lncRNAs) has been found to be a molecular signature behind the pathology of a variety of cancers, including glioma. EIF3J antisense RNA 1 (EIF3J-AS1) is a novel lncRNA, whose performance in carcinogenesis has been unfolded. Nevertheless, the role of EIF3J-AS1 has never been investigated in glioma. Methods: qRT-PCR analysis was adopted to evaluate the relative levels of RNAs. In vitro functional assays, including colony formation, EdU, TUNEL and caspase-3/8/9 activity assays were conducted to study the impacts of EIF3J-AS1 on glioma. Dual-luciferase activity assays, RNA pull down assay and RIP assay were performed to elucidate molecular interplay among genes. Results: EIF3J-AS1 was overexpressed in glioma cell lines. Knockdown of EIF3J-AS1 hampered glioma malignant phenotypes. MiR-1343-3p could bind to EIF3J-AS1. Moreover, miR-1343-3p targeted Annexin A11 (ANXA11) in its 3′UTR region. Mechanistically, EIF3J-AS1 relieved ANXA11 from miR-1343-3p silencing in the EIF3J-AS1/miR-1343-3p/ANXA11 RNA induced silencing complex (RISC), thus eliciting promoting effects on glioma progression. MiR-1343-3p inhibitor and ANXA11 overexpression offset the inhibitory impacts of EIF3J-AS1 silencing on glioma development. Conclusion: EIF3J-AS1/miR-1343-3p/ANXA11 axis significantly affected biological behaviors in glioma, suggesting new therapeutic target for glioma treatment. [ABSTRACT FROM AUTHOR]

Background: In sarcoidosis, the direction and intensity of immunological reactions involved in disease pathophysiology is affected by variation in the genes coding for effector and regulatory molecules with immune functions. This study, therefore, investigates polymorphic variants in genes involved in inflammation, immune reactions, and granuloma formation in context of their plausible association with sarcoidosis, with specific focus on Greek population., Methods: A total of 18 single-nucleotide polymorphisms (SNPs) were genotyped in Greek patients with pulmonary sarcoidosis ( n  = 103) and in healthy Greek control subjects ( n  = 100) using multiplexed MassARRAY (MassARRAY ®) iPLEX assay based on MALDI-TOF mass spectrometry., Results: TGF-β3 rs3917200*G variant was associated with sarcoidosis (OR: 3.04 [95% CI: 1.98-4.69], p  = 2.76*10 -7 ). Further, ANXA11 rs1049550*A variant was associated with sarcoidosis (OR: 0.59 [0.39-0.89], p  = 0.01)., Conclusions: This first study of genetic variation of immune-related genes in Greek patients with sarcoidosis brings to attention a novel disease 'susceptibility' factor: TGF-β3 rs3917200*G allele. It also confirms previously reported 'protective' association between sarcoidosis and functional variant ANXA11 rs1049550*A. Further work is required to validate these findings and to expand investigation of their plausible relationship with clinical course of the disease.

Background: Accumulating evidence has highlighted the potential role of long non-coding RNAs (lncRNAs) in the biological behaviors of hepatocellular carcinoma (HCC). Here, we elucidated the function and possible molecular mechanisms of the effect of lncRNA-AGAP2-AS1 on the biological behaviors of HCC. Methods: EdU, Transwell and flow cytometry were used to determine proliferation, migration, invasion and apoptosis of HCC cells in vitro. The subcutaneous tumor model and lung metastasis mouse model in nude mice was established to detect tumor growth and metastasis of HCC in vivo. The direct binding of miR-16-5p to 3'UTR of ANXA11 was confirmed by luciferase reporter assay. The expression of AGAP2-AS1 and miR-16-5p in HCC specimens and cell lines were detected by real-time PCR. The correlation among AGAP2-AS1 and miR-16-5p were disclosed by a dual-luciferase reporter assay, RIP assay and biotin pull-down assay. Results: Here, we demonstrated that AGAP2-AS1 expression was up-regulated in HCC tissues and cell lines, especially in metastatic and recurrent cases. Gain- and loss-of-function experiments indicated that AGAP2-AS1 promoted cell proliferation, migration, invasion, EMT progression and inhibited apoptosis of HCC cells in vitro and in vivo. Further studies demonstrated that AGAP2-AS1 could function as a competing endogenous RNA (ceRNA) by sponging miR-16-5p in HCC cells. Functionally, gain- and loss-of-function studies showed that miR-16-5p promoted HCC progression and alteration of miR-16-5p abolished the promotive effects of AGAP2-AS1 on HCC cells. Moreover, ANXA11 was identified as direct downstream targets of miR-16-5p in HCC cells, and mediated the functional effects of miR-16-5p and AGAP2-AS1 in HCC, resulting in AKT signaling activation. Clinically, AGAP2-AS1 and miR-16-5p expression were markedly correlated with adverse clinical features and poor prognosis of HCC patients. We showed that hypoxia was responsible for the overexpression of AGAP2-AS1 in HCC. And the promoting effects of hypoxia on metastasis and EMT of HCC cells were reversed by AGAP2-AS1 knockdown. Conclusions: Taken together, this research supports the first evidence that AGAP2-AS1 plays an oncogenic role in HCC via AGAP2-AS1/miR-16-5p/ANXA11/AKT axis pathway and represents a promising therapeutic strategy for HCC patients. [ABSTRACT FROM AUTHOR]

Recent work on the biophysics of proteins with low complexity, intrinsically disordered domains that have the capacity to form biological condensates has profoundly altered the concepts about the pathogenesis of inherited and sporadic neurodegenerative disorders associated with pathological accumulation of these proteins. In the present review, we use the FUS, TDP-43 and A11 proteins as examples to illustrate how missense mutations and aberrant post-translational modifications of these proteins cause amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration (FTLD)., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Long-distance RNA transport enables local protein synthesis at metabolically-active sites distant from the nucleus. This process ensures an appropriate spatial organization of proteins, vital to polarized cells such as neurons. Here, we present a mechanism for RNA transport in which RNA granules "hitchhike" on moving lysosomes. In vitro biophysical modeling, live-cell microscopy, and unbiased proximity labeling proteomics reveal that annexin A11 (ANXA11), an RNA granule-associated phosphoinositide-binding protein, acts as a molecular tether between RNA granules and lysosomes. ANXA11 possesses an N-terminal low complexity domain, facilitating its phase separation into membraneless RNA granules, and a C-terminal membrane binding domain, enabling interactions with lysosomes. RNA granule transport requires ANXA11, and amyotrophic lateral sclerosis (ALS)-associated mutations in ANXA11 impair RNA granule transport by disrupting their interactions with lysosomes. Thus, ANXA11 mediates neuronal RNA transport by tethering RNA granules to actively-transported lysosomes, performing a critical cellular function that is disrupted in ALS., (Published by Elsevier Inc.)

Abstract Mutations in the annexin A11 gene (ANXA11) have been recently identified in British patients and Italian patients with amyotrophic lateral sclerosis (ALS), and their role in other ALS populations remains unclear. The aim of this study was to investigate the ANXA11 mutations in a Taiwanese ALS cohort. Mutational analysis of ANXA11 was performed in 286 unrelated Taiwanese patients with ALS by Sanger sequencing. Eight ANXA11 missense variants were identified initially, and only one of them was absent from population databases. This missense variant, p.Q362L, was identified in 1 single patient with apparently sporadic ALS, and no further strong evidence was available to support its pathogenicity. Therefore, it is classified as a variant of uncertain significance. Our data indicate that pathogenic ANXA11 mutations are absent or rare in ALS patients in Taiwan. [ABSTRACT FROM AUTHOR]