The transcriptome characteristics of vestibular organs from delayed endolymphatic hydrops patients (Meniere’s disease)

Chen, Binjun; Luo, Wenjing; Zhang, Weidong; Qian, Xiangping; Wang, Yanmei; Zheng, Yu; Wang, Xinwei; Xu, Xinda; Yuan, Yasheng; Chi, Fang‐Lu

doi:10.1111/coa.13748

Cited by 3 publications

(3 citation statements)

References 25 publications

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“…A number of recent studies have highlighted a novel intriguing function of P2 in human astrocytes [2,10], while it is absent from mouse astrocytes. Altered PMP2 expression patterns have been observed in various cancers [10][11][12], as well as in pathological conditions of the inner ear [13].…”

Section: Introductionmentioning

confidence: 99%

Human myelin protein P2: from crystallography to time‐lapse membrane imaging and neuropathy‐associated variants

et al. 2021

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Peripheral myelin protein 2 (P2) is a fatty acid-binding protein expressed in vertebrate peripheral nervous system myelin, as well as in human astrocytes. Suggested functions of P2 include membrane stacking and lipid transport. Mutations in the PMP2 gene, encoding P2, are associated with Charcot-Marie-Tooth disease (CMT). Recent studies have revealed three novel PMP2 mutations in CMT patients. To shed light on the structure and function of these P2 variants, we used X-ray and neutron crystallography, small-angle X-ray scattering, circular dichroism spectroscopy, computer simulations and lipid binding assays. The crystal and solution structures of the I50del, M114T and V115A variants of P2 showed minor differences to the wild-type protein, whereas their thermal stability was reduced. Vesicle aggregation assays revealed no change in membrane stacking characteristics, while the variants showed altered fatty acid binding. Time-lapse imaging of lipid bilayers indicated formation of doublemembrane structures induced by P2, which could be related to its function in stacking of two myelin membrane surfaces in vivo. In order to better understand the links between structure, dynamics and function, the crystal structure of perdeuterated P2 was refined from room temperature data using neutrons and X-rays, and the results were compared to simulations and cryocooled crystal structures. Our data indicate similar properties for all known human P2 CMT variants; while crystal structures are nearly identical, thermal stability and function of CMT variants are impaired. Our data provide new insights into the structure-function relationships and dynamics of P2 in health and disease.

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Section: Introductionmentioning

confidence: 99%

Human myelin protein P2: from crystallography to time‐lapse membrane imaging and neuropathy‐associated variants

et al. 2021

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“…Previous expression studies in MD have involved targeted gene expression [ 18 , 19 ] or small case series [ 9 , 20 , 21 ]. Shew et al [ 19 ] identified a downregulated miRNA in MD patients’ serum and perilymph linked to inflammatory and autoimmune pathways, using a miRNA array for the study of 5 MD patients and 5 controls.…”

Section: Introductionmentioning

confidence: 99%

“…Shew et al [ 19 ] identified a downregulated miRNA in MD patients’ serum and perilymph linked to inflammatory and autoimmune pathways, using a miRNA array for the study of 5 MD patients and 5 controls. Chen et al [ 20 ] performed RNA sequencing on the intact vestibular system of 5 delayed endolymphatic hydrops/ delayed MD patients, and Sun et al [ 21 ] studied the transcriptome of peripheral blood mononuclear cells (PBMC) from three unilateral MD type 1 patients. Despite the low sample size, both found the involvement of immune factors in the disease pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Cytokine profiling and transcriptomics in mononuclear cells define immune variants in Meniere Disease

Flook,

Rojano,

Gallego-Martinez

et al. 2024

Genes Immun

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Meniere Disease (MD) is a chronic inner ear disorder characterized by vertigo attacks, sensorineural hearing loss, tinnitus, and aural fullness. Extensive evidence supporting the inflammatory etiology of MD has been found, therefore, by using transcriptome analysis, we aim to describe the inflammatory variants of MD. We performed Bulk RNAseq on 45 patients with definite MD and 15 healthy controls. MD patients were classified according to their basal levels of IL-1β into 2 groups: high and low. Differentially expression analysis was performed using the ExpHunter Suite, and cell type proportion was evaluated using the estimation algorithms xCell, ABIS, and CIBERSORTx. MD patients showed 15 differentially expressed genes (DEG) compared to controls. The top DEGs include IGHG1 (p = 1.64 $$\times$$ × 10−6) and IGLV3-21 (p = 6.28 $$\times$$ × 10−3), supporting a role in the adaptative immune response. Cytokine profiling defines a subgroup of patients with high levels of IL-1β with up-regulation of IL6 (p = 7.65 $$\times$$ × 10−8) and INHBA (p = 3.39 $$\times$$ × 10−7) genes. Transcriptomic data from peripheral blood mononuclear cells support a proinflammatory subgroup of MD patients with high levels of IL6 and an increase in naïve B-cells, and memory CD8+ T cells.

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Human myelin protein P2: From crystallography to time-lapse membrane imaging and neuropathy-associated variants

Uusitalo

Klenow

Laulumaa

et al. 2021

Preprint

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Peripheral myelin protein 2 (P2) is a fatty acid-binding protein expressed in vertebrate peripheral nervous system myelin, as well as in human astrocytes. Suggested functions of P2 include membrane stacking and lipid transport. Mutations in the PMP2 gene, encoding P2, are associated with Charcot-Marie-Tooth disease (CMT). Recent studies have revealed three novel PMP2 mutations in CMT patient families. To shed light on the structure and function of the corresponding P2 variants, we used X-ray and neutron crystallography, small-angle X-ray scattering, circular dichroism spectroscopy, computer simulations, and lipid binding assays. The crystal and solution structures of the I50del, M114T, and V115A variants of P2 showed only minor differences to the wild-type protein, whereas the thermal stability of the disease variants was reduced. Lipid vesicle aggregation assays revealed no change in membrane stacking characteristics, while the variants showed slightly altered fatty acid binding. Time-lapse imaging of lipid bilayers indicated membrane blebbing induced by P2, which could be related to its function in stacking of two curved membrane surfaces in myelin in vivo. All variants caused blebbing of membranes on similar timescales. In order to better understand the links between structure, dynamics, and function, the crystal structure of perdeuterated P2 was refined from room temperature data collected using both neutrons and X-rays, and the results were compared to molecular dynamics simulations and cryocooled crystal structures. Taken together, our data indicate similar properties of all known CMT variants of human P2; while crystal structures are nearly identical, stability and function of the disease variants are impaired compared to the wild-type protein. Our data provide new insights into the structure-function relationships and dynamics of P2 in health and disease.

show abstract

The transcriptome characteristics of vestibular organs from delayed endolymphatic hydrops patients (Meniere’s disease)

Cited by 3 publications

References 25 publications

Human myelin protein P2: from crystallography to time‐lapse membrane imaging and neuropathy‐associated variants

Human myelin protein P2: from crystallography to time‐lapse membrane imaging and neuropathy‐associated variants

Cytokine profiling and transcriptomics in mononuclear cells define immune variants in Meniere Disease

Human myelin protein P2: From crystallography to time-lapse membrane imaging and neuropathy-associated variants

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