SLC44A2 single nucleotide polymorphisms, isoforms, and expression: Association with severity of Meniere's disease?

Nair, Thankam S.; Kommareddi, Pavan K.; Galano, Maria M.; Miller, Danielle M.; Kakaraparthi, Bala Naveen; Telian, Steven A.; Arts, HH; El-Kashlan, Hussam K.; Kilijanczyk, Alyse; Lassig, Amy Anne D.; Graham, Martin P.; Fisher, Susan G.; Stoll, Stefan; Nair, Rajan P.; Elder, James T.; Carey, Thomas E.

doi:10.1016/j.ygeno.2016.11.002

Cited by 16 publications

(22 citation statements)

References 42 publications

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“…respectively (Nair et al, 2016). We sourced antibodies against SLC44A2 that specifically recognize amino acid sequences within the first and second extracellular loops.…”

Section: Platelet Binding To Vwf Under Flow Induces Intraplatelet Sigmentioning

confidence: 99%

Activated αIIbβ3 on platelets mediates flow-dependent NETosis via SLC44A2

Constantinescu‐Bercu

Grassi

Frontini

et al. 2020

eLife

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Platelet-neutrophil interactions are important for innate immunity, but also contribute to the pathogenesis of deep vein thrombosis, myocardial infarction and stroke. Here we report that, under flow, von Willebrand factor/glycoprotein Ibα-dependent platelet ‘priming’ induces integrin αIIbβ3 activation that, in turn, mediates neutrophil and T-cell binding. Binding of platelet αIIbβ3 to SLC44A2 on neutrophils leads to mechanosensitive-dependent production of highly prothrombotic neutrophil extracellular traps. A polymorphism in SLC44A2 (rs2288904-A) present in 22% of the population causes an R154Q substitution in an extracellular loop of SLC44A2 that is protective against venous thrombosis results in severely impaired binding to both activated αIIbβ3 and VWF-primed platelets. This was confirmed using neutrophils homozygous for the SLC44A2 R154Q polymorphism. Taken together, these data reveal a previously unreported mode of platelet-neutrophil crosstalk, mechanosensitive NET production, and provide mechanistic insight into the protective effect of the SLC44A2 rs2288904-A polymorphism in venous thrombosis.

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“…respectively (Nair et al, 2016). We sourced antibodies against SLC44A2 that specifically recognize amino acid sequences within the first and second extracellular loops.…”

Section: Platelet Binding To Vwf Under Flow Induces Intraplatelet Sigmentioning

confidence: 99%

Activated αIIbβ3 on platelets mediates flow-dependent NETosis via SLC44A2

Constantinescu‐Bercu

Grassi

Frontini

et al. 2020

eLife

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“…and 18a.a. in length, respectively (Nair et al, 2016). We sourced antibodies against SLC44A2 that specifically recognize amino acid sequences within the first and second extracellular loops.…”

Section: 'Primed' Platelets Interact With Slc44a2 Receptor On Neutropmentioning

confidence: 99%

Activated α_IIbβ₃on platelets mediates flow-dependent NETosis via SLC44A2

Constantinescu‐Bercu

Grassi

Frontini

et al. 2018

Preprint

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Platelet-leukocyte interactions are important for innate immune responses, but also contribute to the pathogenesis of thrombotic disorders, such as deep vein thrombosis. How these interactions are manifest and how they influence leukocyte function remains poorly understood. Here, we demonstrate that binding to von Willebrand factor under flow through glycoprotein Ib 'primes' platelets resulting in intracellular Ca 2+ release and  IIb  3 activation. This priming enables platelets to bind leukocytes via a mechanism that is largely independent of P-selectin, but that is inhibited by blocking  IIb  3 . We show that neutrophils and T-cells bind directly to activated  IIb  3 under flow, identifying this platelet integrin as a novel leukocyte receptor. Binding of neutrophils to  IIb  3 under flow causes rapid intracellular Ca 2+ release, and initiates Ca 2+ -and NADPH oxidase-dependent signaling leading to production of neutrophil extracellular traps (NETs). NET production is itself dependent upon a mechanosensitive mechanism, as NETosis is markedly diminished if neutrophils are captured by  IIb  3 under static conditions. Takentogether, these data demonstrate a novel mechanism for platelet-neutrophil cross-talk and mechanosensitive NET production.

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“…NOS3 is also located in the inner and outer hair cells, and a polymorphism of NOS3 (rs1799983) was significantly associated with the risk of sudden SNHL and MD (13). The SLC44A2 encodes a choline transporterlike protein 2 (CTL2) which plays a role in choline transport or uptake with CTL1 (32). Two polymorphisms in SLC44A2 (rs2288904, rs9797861) were linked to venous thrombosis, coronary artery disease, and stroke, and rs2288904 was associated with severity of MD (32).…”

Section: Discussionmentioning

confidence: 99%

“…The SLC44A2 encodes a choline transporterlike protein 2 (CTL2) which plays a role in choline transport or uptake with CTL1 (32). Two polymorphisms in SLC44A2 (rs2288904, rs9797861) were linked to venous thrombosis, coronary artery disease, and stroke, and rs2288904 was associated with severity of MD (32). Furthermore, in vivo binding of anti-SLC44A2 antibody induced hearing loss in mice and guinea pigs (78,79).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, in vivo binding of anti-SLC44A2 antibody induced hearing loss in mice and guinea pigs (78,79). Thus, their genetic deficiency may cause the increased permeability of vascular endothelial cells, oxidative stress response, and increased vascular resistance, resulting in thrombosis and disturbance of micro-circulation in the inner ear (32). Although the diagnostic criteria established by the Classification Committee of the Barany Society may improve the accuracy in clinical diagnosis of MD, the phenotypic heterogeneity is observed and some patients may have comorbid conditions with MD, such as migraine or autoimmune disorders (39).…”

Section: Discussionmentioning

confidence: 99%

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Rare Variants of Putative Candidate Genes Associated With Sporadic Meniere's Disease in East Asian Population

Shin

Kim

et al. 2020

Front. Neurol.

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Objectives: The cause of Meniere's disease (MD) is unclear but likely involves genetic and environmental factors. The aim of this study was to investigate the genetic basis underlying MD by screening putative candidate genes for MD. Methods: Sixty-eight patients who met the diagnostic criteria for MD of the Barany Society were included. We performed targeted gene sequencing using next generation sequencing (NGS) panel composed of 45 MD-associated genes. We identified the rare variants causing non-synonymous amino acid changes, stop codons, and insertions/deletions in the coding regions, and excluded the common variants with minor allele frequency >0.01 in public databases. The pathogenicity of the identified variants was analyzed by various predictive tools and protein structural modeling. Results: The average read depth for the targeted regions was 1446.3-fold, and 99.4% of the targeted regions were covered by 20 or more reads, achieving the high quality of the sequencing. After variant filtering, annotation, and interpretation, we identified a total of 15 rare heterozygous variants in 12 (17.6%) sporadic patients. Among them, four variants were detected in familial MD genes (DTNA, FAM136A, DPT), and the remaining 11 in MD-associated genes (PTPN22, NFKB1, CXCL10, TLR2, MTHFR, SLC44A2, NOS3, NOTCH2). Three patients had the variants in two or more genes. All variants were not detected in our healthy controls (n = 100). No significant differences were observed between patients with and without a genetic variant in terms of sex, mean age of onset, bilaterality, the type of MD, and hearing threshold at diagnosis. Conclusions: Our study identified rare variants of putative candidate genes in some of MD patients. The genes were related to the formation of inner ear structures, the immune-associated process, or systemic hemostasis derangement, suggesting the multiple genetic predispositions in the development of MD.

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SLC44A2 single nucleotide polymorphisms, isoforms, and expression: Association with severity of Meniere's disease?

Cited by 16 publications

References 42 publications

Activated αIIbβ3 on platelets mediates flow-dependent NETosis via SLC44A2

Activated αIIbβ3 on platelets mediates flow-dependent NETosis via SLC44A2

Activated α_IIbβ₃on platelets mediates flow-dependent NETosis via SLC44A2

Rare Variants of Putative Candidate Genes Associated With Sporadic Meniere's Disease in East Asian Population

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SLC44A2 single nucleotide polymorphisms, isoforms, and expression: Association with severity of Meniere's disease?

Cited by 16 publications

References 42 publications

Activated αIIbβ3 on platelets mediates flow-dependent NETosis via SLC44A2

Activated αIIbβ3 on platelets mediates flow-dependent NETosis via SLC44A2

Activated αIIbβ3on platelets mediates flow-dependent NETosis via SLC44A2

Rare Variants of Putative Candidate Genes Associated With Sporadic Meniere's Disease in East Asian Population

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Activated α_IIbβ₃on platelets mediates flow-dependent NETosis via SLC44A2