Variants of <scp><i>LRP2</i></scp>, encoding a multifunctional cell‐surface endocytic receptor, associated with hearing loss and retinal dystrophy

Faridi, Rabia; Yousaf, Rizwan; Gu, Shoujun; Inagaki, Sayaka; Turriff, Amy; Pelstring, Keith; Guan, Bin; Naik, Amelia; Griffith, Andrew J.; Adadey, Samuel Mawuli; Aboagye, Elvis Twumasi; Awandare, Gordon A.; Morell, Robert J.; Tsilou, Ekaterini; Noyes, Amanda G; Sulmonte, Laura A G; Wonkam, Ambroise; Schrauwen, Isabelle; Leal, Suzanne M.; Azaiez, Héla; Brewer, Carmen C.; Riazuddin, Sheikh; Hufnagel, Robert B.; Hoa, Michael; Zein, Wadih M.; Dios, John Karl L. de; Friedman, Thomas B.

doi:10.1111/cge.14312

Cited by 4 publications

(2 citation statements)

References 17 publications

(40 reference statements)

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“…Lrp2, Igf1, and Dclk1 were downregulated in the whole cochlea of aging mice [ 24 ], which is consistent with the findings of He et al [ 32 ] that Igf1 is downregulated in aging mouse hair cells. Lrp2 is expressed enormously in the MC in mouse cochlea and this was identified by smFISH, single-cell and single-nucleus RNAseq in 2023 [ 33 ]. Padi2 and Gas2 were found to be downregulated in the vasculature of cisplatin-treated mice [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of common stria vascularis cellular alteration in sensorineural hearing loss based on ScRNA-seq

Gu,

Jiang,

Chen

et al. 2024

BMC Genomics

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Background The stria vascularis (SV), located in the lateral wall of the cochlea, maintains cochlear fluid homeostasis and mechanoelectrical transduction (MET) activity required for sound wave conduction. The pathogenesis of a number of human inheritable deafness syndromes, age related hearing loss, drug-induced ototoxicity and noise-induced hearing loss results from the morphological changes and functional impairments in the development of the SV. In this study, we investigate the implications of intercellular communication within the SV in the pathogenesis of sensorineural hearing loss (SNHL). We aim to identify commonly regulated signaling pathways using publicly available single-cell transcriptomic sequencing (scRNA-seq) datasets. Methods We analyzed scRNA-seq data, which was derived from studying the cochlear SV in mice with SNHL compared to normal adult mice. After quality control and filtering, we obtained the major cellular components of the mouse cochlear SV and integrated the data. Using Seurat's FindAllMarkers and FindMarkers packages, we searched for novel conservative genes and differential genes. We employed KEGG and GSEA to identify molecular pathways that are commonly altered among different types of SNHL. We utilized pySCENIC to discover new specific regulatory factors in SV subpopulation cells. With the help of CellChat, we identified changes in subpopulation cells showing similar trends across different SNHL types and their alterations in intercellular communication pathways. Results Through the analysis of the integrated data, we discovered new conserved genes to SV specific cells and identified common downregulated pathways in three types of SNHL. The enriched genes for these pathways showing similar trends are primarily associated with the Electron Transport Chain, related to mitochondrial energy metabolism. Using the CellChat package, we further found that there are shared pathways in the incoming signaling of specific intermediate cells in SNHL, and these pathways have common upstream regulatory transcription factor of Nfe2l2. Combining the results from pySCENIC and CellChat, we predicted the transcription factor Nfe2l2 as an upstream regulatory factor for multiple shared cellular pathways in IC. Additionally, it serves as an upstream factor for several genes within the Electron Transport Chain. Conclusion Our bioinformatics analysis has revealed that downregulation of the mitochondrial electron transport chain have been observed in various conditions of SNHL. E2f1, Esrrb, Runx1, Yy1, and Gata2 could serve as novel important common TFs regulating the electron transport chain. Adm has emerged as a potential new marker gene for intermediate cells, while Itgb5 and Tesc show promise as potential new marker genes for marginal cells in the SV. These findings offer a new perspective on SV lesions in SNHL and provide additional theoretical evidence for the same drug treatment and prevention of different pathologies of SNHL.

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Section: Discussionmentioning

confidence: 99%

Identification of common stria vascularis cellular alteration in sensorineural hearing loss based on ScRNA-seq

Gu,

Jiang,

Chen

et al. 2024

BMC Genomics

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“…Specifically, among female-biased genes across taxa, SLC6A2 overlapped between R. pusillus and R. sinicus, which is one of the ADHD risk genes in humans and has also been identified to have sexually dimorphic effects with a greater effect on females than on males [65]. Another notable gene is LRP2 overlapped between R. pusillus and R. affinis hainanus, which was identified as a deafness gene [66,67] as well as a candidate echolocation gene associated with the origin of laryngeal echolocation in bats [60]. A previous study also showed that LRP2 can partially mediate a female-specific effects of LCN2 on metabolic traits in mice [68].…”

Section: Discussionmentioning

confidence: 99%

Sex Differences in Cochlear Transcriptomes in Horseshoe Bats

Wu,

Duan,

Lan

et al. 2024

Animals

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Sexual dimorphism of calls is common in animals, whereas studies on the molecular basis underlying this phenotypic variation are still scarce. In this study, we used comparative transcriptomics of cochlea to investigate the sex-related difference in gene expression and alternative splicing in four Rhinolophus taxa. Based on 31 cochlear transcriptomes, we performed differential gene expression (DGE) and alternative splicing (AS) analyses between the sexes in each taxon. Consistent with the degree of difference in the echolocation pulse frequency between the sexes across the four taxa, we identified the largest number of differentially expressed genes (DEGs) and alternatively spliced genes (ASGs) in R. sinicus. However, we also detected multiple DEGs and ASGs in taxa without sexual differences in echolocation pulse frequency, suggesting that these genes might be related to other parameters of echolocation pulse rather than the frequency component. Some DEGs and ASGs are related to hearing loss or deafness genes in human or mice and they can be considered to be candidates associated with the sexual differences of echolocation pulse in bats. We also detected more than the expected overlap of DEGs and ASGs in two taxa. Overall, our current study supports the important roles of both DGE and AS in generating or maintaining sexual differences in animals.

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Clinical Genetic Testing for Hearing Loss: Implications for Genetic Counseling and Gene-Based Therapies

Lee,

Uhler,

Yoon

et al. 2024

Biomedicines

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Genetic factors contribute significantly to congenital hearing loss, with non-syndromic cases being more prevalent and genetically heterogeneous. Currently, 150 genes have been associated with non-syndromic hearing loss, and their identification has improved our understanding of auditory physiology and potential therapeutic targets. Hearing loss gene panels offer comprehensive genetic testing for hereditary hearing loss, and advancements in sequencing technology have made genetic testing more accessible and affordable. Currently, genetic panel tests available at a relatively lower cost are offered to patients who face financial barriers. In this study, clinical and audiometric data were collected from six pediatric patients who underwent genetic panel testing. Known pathogenic variants in MYO15A, GJB2, and USH2A were most likely to be causal of hearing loss. Novel pathogenic variants in the MYO7A and TECTA genes were also identified. Variable hearing phenotypes and inheritance patterns were observed amongst individuals with different pathogenic variants. The identification of these variants contributes to the continually expanding knowledge base on genetic hearing loss and lays the groundwork for personalized treatment options in the future.

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Variants of LRP2, encoding a multifunctional cell‐surface endocytic receptor, associated with hearing loss and retinal dystrophy

Cited by 4 publications

References 17 publications

Identification of common stria vascularis cellular alteration in sensorineural hearing loss based on ScRNA-seq

Identification of common stria vascularis cellular alteration in sensorineural hearing loss based on ScRNA-seq

Sex Differences in Cochlear Transcriptomes in Horseshoe Bats

Clinical Genetic Testing for Hearing Loss: Implications for Genetic Counseling and Gene-Based Therapies

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