Resident Physician and Postdoctoral Fellow in the Department of Otolaryngology - Head & Neck Surgery
NIH T32 Clinician-Scientist Training Program
MD, The Johns Hopkins University School of Medicine (2017)
BA, Rice University, Biochemistry & Cell Biology (2012)
SLC26A4-linked CEVA haplotype correlates with phenotype in patients with enlargement of the vestibular aqueduct.
BMC medical genetics
2019; 20 (1): 118
Recessive mutations of coding regions and splice sites of the SLC26A4 gene cause hearing loss with enlargement of the vestibular aqueduct (EVA). Some patients also have a thyroid iodination defect that can lead to multinodular goiter as part of Pendred syndrome. A haplotype of variants upstream of SLC26A4, called CEVA, acts as a pathogenic recessive allele in trans to mutations affecting the coding regions or splice sites of SLC26A4. Our first hypothesis is that CEVA, acting as a pathogenic recessive allele, is correlated with a less severe phenotype than mutations affecting the coding regions and splice sites of SLC26A4. Our second hypothesis is that CEVA acts as a modifier of the phenotype in patients with EVA caused by mutations affecting the coding regions or splice sites of both alleles of SLC26A4 or EVA caused by other factors.This was a prospective cohort study of 114 individuals and 202 ears with EVA. To test our first hypothesis, we compared the thyroid and auditory phenotypes of subjects with mutations affecting coding regions of both alleles of SLC26A4 with those of subjects carrying CEVA in trans to mutations affecting the coding regions. To test our second hypothesis, we compared the phenotypes associated with the presence versus absence of CEVA among subjects with no coding region mutations, as well as among subjects with mutations affecting coding regions of both alleles.Subjects carrying CEVA in trans to a mutation of SLC26A4 have a normal thyroid phenotype and less severe hearing loss in comparison to individuals with mutations affecting coding regions of both alleles of SLC26A4. In subjects with no mutant alleles of SLC26A4, hearing loss was more severe in subjects who carry the CEVA haplotype in comparison to non-carriers. There was no correlation of CEVA with the phenotype of subjects with mutations affecting coding regions of both alleles.CEVA, acting as a likely pathogenic recessive allele, is associated with a less severe phenotype than alleles with a mutation affecting the coding regions or splice sites of SLC26A4. CEVA may act as a genetic modifier in patients with EVA caused by other factors.
View details for DOI 10.1186/s12881-019-0853-4
View details for PubMedID 31266487
View details for PubMedCentralID PMC6604142
A common SLC26A4-linked haplotype underlying non-syndromic hearing loss with enlargement of the vestibular aqueduct.
Journal of medical genetics
2017; 54 (10): 665–73
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.We performed genotype-haplotype analysis and massively parallel sequencing of the SLC26A4 region in patients with M1 EVA and their families.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).The 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.
View details for DOI 10.1136/jmedgenet-2017-104721
View details for PubMedID 28780564
View details for PubMedCentralID PMC5880640
Use of the Phantom Electrode strategy to improve bass frequency perception for music listening in cochlear implant users.
Cochlear implants international
2015; 16 Suppl 3: S121–8
The Phantom Electrode strategy makes use of partial bipolar stimulation on the two most apical electrodes in an effort to extend the frequency range available to cochlear implant (CI) users. This study aimed to quantify the effect of the Phantom Electrode strategy on bass frequency perception in music listening in CI users.Eleven adult Advanced Bionics users with the Fidelity 120 processing strategy and 16 adult normal hearing (NH) individuals participated in the study. All subjects completed the CI-multiple stimulus with hidden reference and anchor (MUSHRA), a test of an individual's ability to make discriminations in sound quality following the removal of bass frequency information. NH participants completed the CI-MUSHRA once, whereas CI users completed the task twice - once with their baseline clinical program and once with the Phantom Electrode strategy, in random order. CI users' performance was assessed in comparison with NH performance.The Phantom Electrode strategy improved CI users performance on the CI-MUSHRA compared with Fidelity 120.Creation of a Phantom Electrode percept through partial bipolar stimulation of the two most apical electrodes appears to improve CI users' perception of bass frequency information in music, contributing to greater accuracy in the ability to detect alterations in musical sound quality.The Phantom Electrode processing strategy may enhance the experience of listening to music and thus acoustic stimuli more broadly by improving perception of bass frequencies, through direction of current towards the apical portion of the cochlea beyond the termination of the electrode.
View details for DOI 10.1179/1467010015Z.000000000270
View details for PubMedID 26561883
Reverberation negatively impacts musical sound quality for cochlear implant users.
Cochlear implants international
2015; 16 Suppl 3: S105–13
Satisfactory musical sound quality remains a challenge for many cochlear implant (CI) users. In particular, questionnaires completed by CI users suggest that reverberation due to room acoustics can negatively impact their music listening experience. The objective of this study was to more specifically characterize of the effect of reverberation on musical sound quality in CI users, normal hearing (NH) non-musicians, and NH musicians using a previously designed assessment method, called Cochlear Implant-MUltiple Stimulus with Hidden Reference and Anchor (CI-MUSHRA).In this method, listeners were randomly presented with an anechoic musical segment and five-versions of this segment in which increasing amounts of reverberation were artificially added. Participants listened to the six reverberation versions and provided sound quality ratings between 0 (very poor) and 100 (excellent).Results demonstrated that on average CI users and NH non-musicians preferred the sound quality of anechoic versions to more reverberant versions. In comparison, NH musicians could be delineated into those who preferred the sound quality of anechoic pieces and those who preferred pieces with some reverberation.This is the first study, to our knowledge, to objectively compare the effects of reverberation on musical sound quality ratings in CI users. These results suggest that musical sound quality for CI users can be improved by non-reverberant listening conditions and musical stimuli in which reverberation is removed.
View details for DOI 10.1179/1467010015Z.000000000262
View details for PubMedID 26561881
The adhesion-GPCR BAI1 regulates synaptogenesis by controlling the recruitment of the Par3/Tiam1 polarity complex to synaptic sites.
The Journal of neuroscience : the official journal of the Society for Neuroscience
2013; 33 (16): 6964–78
Excitatory synapses are polarized structures that primarily reside on dendritic spines in the brain. The small GTPase Rac1 regulates the development and plasticity of synapses and spines by modulating actin dynamics. By restricting the Rac1-guanine nucleotide exchange factor Tiam1 to spines, the polarity protein Par3 promotes synapse development by spatially controlling Rac1 activation. However, the mechanism for recruiting Par3 to spines is unknown. Here, we identify brain-specific angiogenesis inhibitor 1 (BAI1) as a synaptic adhesion GPCR that is required for spinogenesis and synaptogenesis in mice and rats. We show that BAI1 interacts with Par3/Tiam1 and recruits these proteins to synaptic sites. BAI1 knockdown results in Par3/Tiam1 mislocalization and loss of activated Rac1 and filamentous actin from spines. Interestingly, BAI1 also mediates Rac-dependent engulfment in professional phagocytes through its interaction with a different Rac1-guanine nucleotide exchange factor module, ELMO/DOCK180. However, this interaction is dispensable for BAI1's role in synapse development because a BAI1 mutant that cannot interact with ELMO/DOCK180 rescues spine defects in BAI1-knockdown neurons, whereas a mutant that cannot interact with Par3/Tiam1 rescues neither spine defects nor Par3 localization. Further, overexpression of Tiam1 rescues BAI1 knockdown spine phenotypes. These results indicate that BAI1 plays an important role in synaptogenesis that is mechanistically distinct from its role in phagocytosis. Furthermore, our results provide the first example of a cell surface receptor that targets members of the PAR polarity complex to synapses.
View details for DOI 10.1523/JNEUROSCI.3978-12.2013
View details for PubMedID 23595754
View details for PubMedCentralID PMC3670686