Browsing by Author "Cabrera, Ernesto"

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    Biallelic Loss-of-Function Variants in BICD1 Are Associated with Peripheral Neuropathy and Hearing Loss
    (MDPI, 2023-05-17) Hirsch, Yoel; Chung, Wendy K.; Novoselov, Sergey; Weimer, Louis H.; Rossor, Alexander; LeDuc, Charles A.; McPartland, Amanda J.; Cabrera, Ernesto; Ekstein, Josef; Scher, Sholem; Nelson, Rick F.; Schiavo, Giampietro; Henderson, Lindsay B.; Booth, Kevin T. A.; Otolaryngology -- Head and Neck Surgery, School of Medicine
    Hearing loss and peripheral neuropathy are two clinical entities that are genetically and phenotypically heterogeneous and sometimes co-occurring. Using exome sequencing and targeted segregation analysis, we investigated the genetic etiology of peripheral neuropathy and hearing loss in a large Ashkenazi Jewish family. Moreover, we assessed the production of the candidate protein via western blotting of lysates from fibroblasts from an affected individual and an unaffected control. Pathogenic variants in known disease genes associated with hearing loss and peripheral neuropathy were excluded. A homozygous frameshift variant in the BICD1 gene, c.1683dup (p.(Arg562Thrfs*18)), was identified in the proband and segregated with hearing loss and peripheral neuropathy in the family. The BIDC1 RNA analysis from patient fibroblasts showed a modest reduction in gene transcripts compared to the controls. In contrast, protein could not be detected in fibroblasts from a homozygous c.1683dup individual, whereas BICD1 was detected in an unaffected individual. Our findings indicate that bi-allelic loss-of-function variants in BICD1 are associated with hearing loss and peripheral neuropathy. Definitive evidence that bi-allelic loss-of-function variants in BICD1 cause peripheral neuropathy and hearing loss will require the identification of other families and individuals with similar variants with the same phenotype.
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    TMPRSS3 expression is limited in spiral ganglion neurons: implication for successful cochlear implantation
    (BMJ, 2022) Chen, Yuan-Siao; Cabrera, Ernesto; Tucker, Brady J.; Shin, Timothy J.; Moawad, Jasmine V.; Totten, Douglas J.; Booth, Kevin T.; Nelson, Rick F.; Otolaryngology -- Head and Neck Surgery, School of Medicine
    Background: It is well established that biallelic mutations in transmembrane protease, serine 3 (TMPRSS3) cause hearing loss. Currently, there is controversy regarding the audiological outcomes after cochlear implantation (CI) for TMPRSS3-associated hearing loss. This controversy creates confusion among healthcare providers regarding the best treatment options for individuals with TMPRSS3-related hearing loss. Methods: A literature review was performed to identify all published cases of patients with TMPRSS3-associated hearing loss who received a CI. CI outcomes of this cohort were compared with published adult CI cohorts using postoperative consonant-nucleus-consonant (CNC) word performance. TMPRSS3 expression in mouse cochlea and human auditory nerves (HAN) was determined by using hybridisation chain reaction and single-cell RNA-sequencing analysis. Results: In aggregate, 27 patients (30 total CI ears) with TMPRSS3-associated hearing loss treated with CI, and 85% of patients reported favourable outcomes. Postoperative CNC word scores in patients with TMPRSS3-associated hearing loss were not significantly different than those seen in adult CI cohorts (8 studies). Robust Tmprss3 expression occurs throughout the mouse organ of Corti, the spindle and root cells of the lateral wall and faint staining within <5% of the HAN, representing type II spiral ganglion neurons. Adult HAN express negligible levels of TMPRSS3. Conclusion: The clinical features after CI and physiological expression of TMPRSS3 suggest against a major role of TMPRSS3 in auditory neurons.