Loss of <i>Baiap2l2</i> destabilizes the transducing stereocilia of cochlear hair cells and leads to deafness

Carlton, Adam J; Halford, Julia; Underhill, Anna; Jeng, J; Avenarius, Matthew R.; Gilbert, Merle L.; Ceriani, Federico; Ebisine, Kimimuepigha; Brown, Steve; Bowl, Michael R.; Barr-Gillespie, Peter G.; Marcotti, Walter

doi:10.1113/jp280670

Cited by 33 publications

(57 citation statements)

References 88 publications

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“…Mice from both sexes were used and ranging from postnatal day 4 (P4) to P35. The semicircular canals with their ampullae and cochleae (apical turn) were dissected out from the inner ear as reported previously ( Jeng et al, 2020a , 2021 ; Spaiardi et al, 2020a ; Carlton et al, 2021 ), using an extracellular solution composed of (in mM) 135 NaCl, 5.8 KCl, 1.3 CaCl 2 , 0.9 MgCl 2 , 0.7 NaH 2 PO 4 , 5.6 D -glucose, and 10 HEPES-NaOH. Sodium pyruvate (2 mM), amino acids, and vitamins were added from concentrates (Thermo Fisher Scientific, United Kingdom).…”

Section: Methodsmentioning

confidence: 99%

Current Response in CaV1.3–/– Mouse Vestibular and Cochlear Hair Cells

et al. 2021

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Signal transmission by sensory auditory and vestibular hair cells relies upon Ca2+-dependent exocytosis of glutamate. The Ca2+ current in mammalian inner ear hair cells is predominantly carried through CaV1.3 voltage-gated Ca2+ channels. Despite this, CaV1.3 deficient mice (CaV1.3–/–) are deaf but do not show any obvious vestibular phenotype. Here, we compared the Ca2+ current (ICa) in auditory and vestibular hair cells from wild-type and CaV1.3–/– mice, to assess whether differences in the size of the residual ICa could explain, at least in part, the two phenotypes. Using 5 mM extracellular Ca2+ and near-body temperature conditions, we investigated the cochlear primary sensory receptors inner hair cells (IHCs) and both type I and type II hair cells of the semicircular canals. We found that the residual ICa in both auditory and vestibular hair cells from CaV1.3–/– mice was less than 20% (12–19%, depending on the hair cell type and age investigated) compared to controls, indicating a comparable expression of CaV1.3 Ca2+ channels in both sensory organs. We also showed that, different from IHCs, type I and type II hair cells from CaV1.3–/– mice were able to acquire the adult-like K+ current profile in their basolateral membrane. Intercellular K+ accumulation was still present in CaV1.3–/– mice during IK,L activation, suggesting that the K+-based, non-exocytotic, afferent transmission is still functional in these mice. This non-vesicular mechanism might contribute to the apparent normal vestibular functions in CaV1.3–/– mice.

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Section: Methodsmentioning

confidence: 99%

Current Response in CaV1.3–/– Mouse Vestibular and Cochlear Hair Cells

et al. 2021

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“…Imaging of GWAS-associated genes in human cochlear tissue showed the actin-associated proteins LMO-7, TRIOBP, and NOX4 to all be expressed in the human hair cells, the hair cell cuticulae, and stereocilia. In addition, five additional structural regulators that are expressed in the hair cells, stereocilia, and cuticula in other species were also associated with hearing-related traits in our analyses: SPTBN1 (beta-II spectrin) [78], CDH13 (cadherin-13) [95], BAIAP2L2 (brain-specific angiogenesis inhibitor 1-associated protein 2-like protein 2) [108], FSCN2 (fascin-2) [150], and TPRN (taperin) [97]. Age-related hearing loss has been hypothesized to involve the accumulated damage to the stereocilia and hair cells due to damaging environmental exposures in an individual's lifetime [151].…”

Section: Discussionmentioning

confidence: 72%

A combined genome-wide association and molecular study of age-related hearing loss in H. sapiens

Liu

Johansson

Rask‐Andersen

et al. 2021

BMC Med

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Background Sensorineural hearing loss is one of the most common sensory deficiencies. However, the molecular contribution to age-related hearing loss is not fully elucidated. Methods We performed genome-wide association studies (GWAS) for hearing loss-related traits in the UK Biobank (N = 362,396) and selected a high confidence set of ten hearing-associated gene products for staining in human cochlear samples: EYA4, LMX1A, PTK2/FAK, UBE3B, MMP2, SYNJ2, GRM5, TRIOBP, LMO-7, and NOX4. Results All proteins were found to be expressed in human cochlear structures. Our findings illustrate cochlear structures that mediate mechano-electric transduction of auditory stimuli, neuronal conductance, and neuronal plasticity to be involved in age-related hearing loss. Conclusions Our results suggest common genetic variation to influence structural resilience to damage as well as cochlear recovery after trauma, which protect against accumulated damage to cochlear structures and the development of hearing loss over time.

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“…While the roles of KRT78 and KRT79 haven’t been fully characterized within the brain, the SNP rs89962 has been founded to be associated with increased risk of stroke 47 . Another suggestive hit, BAIAP2L2 (a stereociliary protein found in both inner and outer hair cells) has been shown to have profound effects on hearing loss in mutant mice 48 . While these hits indicate that cellular structure may play a role in predisposing individuals to tinnitus, signaling proteins may also play much more complicated roles that warrant further investigation.…”

Section: Discussionmentioning

confidence: 99%

Genetic predisposition to tinnitus in the UK Biobank population

Urbanek

Zuo

2021

Sci Rep

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Tinnitus, the phantom perception of noise originating from the inner ear, has been reported by 15% of the world’s population, with many patients reporting major deficits to cognition and mood. However, both objective diagnostic tools and targeted therapeutic strategies have yet to be established. To better understand the underlying genes that may preclude tinnitus, we performed a genome-wide association study of the UK Biobank’s 49,960 whole exome sequencing participants to identify any loci strongly associated with tinnitus. We identified 17 suggestive single nucleotide polymorphisms (p < 1e−5) spanning 13 genes in two sex-separated cohorts reporting chronic, bothersome tinnitus (control males n = 7,315, tinnitus males n = 226, control females n = 11,732, tinnitus females n = 300). We also found a significant missense mutation in WDPCP (p = 3.959e−10) in the female cohort, a mutation which has been previously implicated in typical neuronal functioning through axonal migration and structural reinforcement, as well as in Bardet-Biedl syndrome-15, a ciliopathy. Additionally, in situ hybridization in the embryonic and P56 mouse brain demonstrated that the majority of these genes are expressed within the dorsal cochlear nucleus, the region of the brain theorized to initially induce tinnitus. Further RT-qPCR and RNAScope data also reveals this expression pattern. The results of this study indicate that predisposition to tinnitus may span across multiple genomic loci and be established by weakened neuronal circuitry and maladaptive cytoskeletal modifications within the dorsal cochlear nucleus.

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Loss of Baiap2l2 destabilizes the transducing stereocilia of cochlear hair cells and leads to deafness

Cited by 33 publications

References 88 publications

Current Response in CaV1.3–/– Mouse Vestibular and Cochlear Hair Cells

Current Response in CaV1.3–/– Mouse Vestibular and Cochlear Hair Cells

A combined genome-wide association and molecular study of age-related hearing loss in H. sapiens

Genetic predisposition to tinnitus in the UK Biobank population

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