Slc26a4 expression prevents fluctuation of hearing in a mouse model of large vestibular aqueduct syndrome

Nishio, Ayako; Ito, Taku; Cheng, Hui; Fitzgerald, Tracy S.; Wangemann, Philine; Griffith, Andrew J.

doi:10.1016/j.neuroscience.2016.04.042

“…This difference in expression would be difficult to detect with conventional measures of RNA levels. Furthermore, alternative transcription initiation sites and alternative splicing resulting in a family of shorter transcripts may contribute to complex regulation and function of the ‘full-length’ transcript 26. Finally, inner ear tissue from human patients is not accessible for research purposes, and peripheral leucocytes express SLC26A4 at low levels that cannot be reliably measured or compared (unpublished observations).…”

Section: Discussionmentioning

confidence: 99%

A commonSLC26A4-linked haplotype underlying non-syndromic hearing loss with enlargement of the vestibular aqueduct

Chattaraj

¹

,

Munjal

²

,

Honda

³

et al. 2017

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Background Enlargement of the vestibular aqueduct (EVA) is the most common radiological abnormality in children with sensorineural hearing loss. Mutations in coding regions and splice sites of the SLC26A4 gene are often detected in Caucasians with EVA. Approximately one-fourth of patients with EVA have two mutant alleles (M2), one-fourth have one mutant allele (M1) and one-half have no mutant alleles (M0). The M2 genotype is correlated with a more severe phenotype. Methods We performed genotype–haplotype analysis and massively parallel sequencing of the SLC26A4 region in patients with M1 EVA and their families. Results We identified a shared novel haplotype, termed CEVA (Caucasian EVA), composed of 12 uncommon variants upstream of SLC26A4. The presence of the CEVA haplotype on seven of ten ’mutation-negative’ chromosomes in a National Institutes of Health M1 EVA discovery cohort and six of six mutation-negative chromosomes in a Danish M1 EVA replication cohort is higher than the observed prevalence of 28 of 1006 Caucasian control chromosomes (p<0.0001 for each EVA cohort). The corresponding heterozygous carrier rate is 28/503 (5.6%). The prevalence of CEVA (11 of 126) is also increased among M0 EVA chromosomes (p=0.0042). Conclusions T he CEVA haplotype causally contributes to most cases of Caucasian M1 EVA and, possibly, some cases of M0 EVA. The CEVA haplotype of SLC26A4 defines the most common allele associated with hereditary hearing loss in Caucasians. The diagnostic yield and prognostic utility of sequence analysis of SLC26A4 exons and splice sites will be markedly increased by addition of testing for the CEVA haplotype.

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“…Here, we will focus the analyses on the marginal, intermediate, basal, and spindle/root cell clusters. Feature plots of both scRNA-Seq and snRNA-Seq datasets demonstrate the correlation of known gene expression for marginal cells (Kcne1, Kcnq1) (Wangemann, 2002), intermediate cells (Cd44, Met) (Shibata et al, 2016;Rohacek et al, 2017), basal cells (Cldn11, Tjp1) (Gow, 2004;Lee et al, 2017;Liu et al, 2017), and spindle/root cells (Slc26a4) between the two datasets ( Figures 2B,D) (Nishio et al, 2016). Violin plots demonstrate relative expression of these known SV cell type-specific genes across the four main cell types (Figures 2C,E).…”

Section: Stria Vascularis (Sv) Cell Types Exhibit Clear Transcriptionmentioning

confidence: 96%

Single Cell and Single Nucleus RNA-Seq Reveal Cellular Heterogeneity and Homeostatic Regulatory Networks in Adult Mouse Stria Vascularis

Korrapati

¹

,

Taukulis

²

,

Olszewski

³

et al. 2019

Front. Mol. Neurosci.

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The stria vascularis (SV) generates the endocochlear potential (EP) in the inner ear and is necessary for proper hair cell mechanotransduction and hearing. While channels belonging to SV cell types are known to play crucial roles in EP generation, relatively little is known about gene regulatory networks that underlie the ability of the SV to generate and maintain the EP. Using single cell and single nucleus RNA-sequencing, we identify and validate known and rare cell populations in the SV. Furthermore, we establish a basis for understanding molecular mechanisms underlying SV function by identifying potential gene regulatory networks as well as druggable gene targets. Finally, we associate known deafness genes with adult SV cell types. This work establishes a basis for dissecting the genetic mechanisms underlying the role of the SV in hearing and will serve as a basis for designing therapeutic approaches to hearing loss related to SV dysfunction.

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“…Feature plots of both scRNA-Seq and snRNA-Seq datasets demonstrate the correlation of known gene expression for marginal cells (Kcne1, Kcnq1) (Wangemann, 2002), intermediate cells (Cd44, Met) (Rohacek et al, 2017;Shibata, Miwa, Wu, Levitt, & Ohyama, 2016), basal cells (Cldn11, Tjp1) (Gow, 2004;Lee, Shin, Sagong, Kim, & Bok, 2017;W. Liu, Schrott-Fischer, Glueckert, Benav, & Rask-Andersen, 2017), and spindle/root cells (Slc26a4) between the two datasets ( Figure 2B, 2D) (Nishio et al, 2016). Violin plots demonstrate relative expression of these known SV cell type-specific genes across the 4 main cell types ( Figure 2C, 2E).…”

Section: Stria Vascularis (Sv) Cell Types Exhibit Clear Transcriptionmentioning

confidence: 97%

Single cell and single nucleus RNA-Seq reveal cellular heterogeneity and homeostatic regulatory networks in adult mouse stria vascularis

Korrapati

¹

,

Taukulis

²

,

Olszewski

³

et al. 2019

Preprint

1

0

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The stria vascularis (SV) generates the endocochlear potential (EP) in the inner ear and is necessary for proper hair cell mechanotransduction and hearing. While channels belonging to SV cell types are known to play crucial roles in EP generation, relatively little is known about gene regulatory networks that underlie the ability of the SV to generate and maintain the EP. Using single cell and single nucleus RNA-sequencing, we identify and validate known and rare cell populations in the SV. Furthermore, we establish a basis for understanding molecular mechanisms underlying SV function by identifying potential gene regulatory networks as well as druggable gene targets. Finally, we associate known deafness genes with adult SV cell types. This work establishes a basis for dissecting the genetic mechanisms underlying the role of the SV in hearing and will serve as a basis for designing therapeutic approaches to hearing loss related to SV dysfunction.

show abstract

Slc26a4 expression prevents fluctuation of hearing in a mouse model of large vestibular aqueduct syndrome

Cited by 30 publications

References 20 publications

A commonSLC26A4-linked haplotype underlying non-syndromic hearing loss with enlargement of the vestibular aqueduct

A commonSLC26A4-linked haplotype underlying non-syndromic hearing loss with enlargement of the vestibular aqueduct

Single Cell and Single Nucleus RNA-Seq Reveal Cellular Heterogeneity and Homeostatic Regulatory Networks in Adult Mouse Stria Vascularis

Single cell and single nucleus RNA-Seq reveal cellular heterogeneity and homeostatic regulatory networks in adult mouse stria vascularis

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