Seyra Erbek

A Truncating Mutation in SERPINB6 Is Associated with Autosomal-Recessive Nonsyndromic Sensorineural Hearing Loss

More than 270 million people worldwide have hearing loss that affects normal communication. Although astonishing progress has been made in the identification of more than 50 genes for deafness during the past decade, the majority of deafness genes are yet to be identified. In this study, we mapped a previously unknown autosomal-recessive nonsyndromic sensorineural hearing loss locus (DFNB91) to chromosome 6p25 in a consanguineous Turkish family. The degree of hearing loss was moderate to severe in affected individuals. We subsequently identified a nonsense mutation (p.E245X) in SERPINB6, which is located within the linkage interval for DFNB91 and encodes for an intracellular protease inhibitor. The p.E245X mutation cosegregated in the family as a completely penetrant autosomal-recessive trait and was absent in 300 Turkish controls. The mRNA expression of SERPINB6 was reduced and production of protein was absent in the peripheral leukocytes of homozygotes, suggesting that the hearing loss is due to loss of function of SERPINB6. We also demonstrated that SERPINB6 was expressed primarily in the inner ear hair cells. We propose that SERPINB6 plays an important role in the inner ear in the protection against leakage of lysosomal content during stress and that loss of this protection results in cell death and sensorineural hearing loss.

Recurrent and private MYO15A mutations are associated with deafness in the Turkish population.

The identities and frequencies of MYO15A mutations associated with hearing loss in different populations remained largely unknown. We screened the MYO15A gene for mutations in 104 unrelated multiplex and consanguineous Turkish families with autosomal recessive nonsyndromic sensorineural hearing loss using autozygosity mapping. The screening of MYO15A in 10 families mapped to the DFNB3 locus revealed five previously unreported mutations: p.Y289X (1 family), p.V1400M (1 family), p.S1481P (1 family), p.R1937TfsX10 (3 families), and p.S3335AfsX121 (2 families). Recurrent mutations were associated with conserved haplotypes suggesting the presence of founder effects. Severe to profound sensorineural hearing loss was observed in all subjects with homozygous mutations except for two members of a family who were homozygous for the p.Y289X mutation in the N-terminal extension domain and had considerable residual hearing. We estimate the prevalence of homozygous MYO15A mutations in autosomal recessive nonsyndromic deafness in Turkey as 0.062 (95% confidence interval is 0.020-0.105).

The role of allergy in the severity of nasal polyposis.

Background Although patients with nasal polyposis frequently exhibit concomitant allergy, there is limited information about the impact of allergy on the severity of nasal polyposis. The goal of this study was to evaluate the role of allergy in the severity of nasal polyposis. Methods Polyp sizes, computed tomography (CT) scores, skin-prick test results, blood total eosinophil count, serum levels of total immunoglobulin E, symptom scores, and recurrences were analyzed in 83 patients with nasal polyposis. The results were compared between allergic and nonallergic patients with nasal polyposis. Results No association was found between the presence of allergy per skin-prick testing and polyp size, CT opacification, symptom scores, or recurrences (p > 0.05). In allergic patients, only the serum total eosinophil count correlated strongly with the results of CT (p = 0.005) but not with other parameters (p > 0.05). Conclusions The results of this study show that, although patients with nasal polyposis frequently have allergies, the presence of allergy does not correlate with polyp size, symptom scores or rate of recurrence.

Expression of a disintegrin and metalloproteinase 33 protein in nasal polyposis: an immunohistochemical study.

Background A disintegrin and metalloproteinase (ADAM)-33 is a member of matrix metalloproteinases. This protein takes a role in angiogenesis and airway remodeling in asthma. Because histopathological findings of airway remodeling in asthma and nasal polyposis (NP) are similar, the aim of this study was to evaluate the ADAM-33 expression in NP. Methods Immunohistochemical staining of specimens of 47 patients with NP and 8 patients with concha bullosa was performed to detect the expression of ADAM-33. Paraffin blocks were used to identify the expression of ADAM-33 polyclonal antibodies. Immunostaining of epithelial cells, stroma, mesenchymal cells of vessels, and inflammatory cells were analyzed by using light microscopy. Results Immunopositivity scores in epithelial cells in NP (median, 2; range, 1–3) were significantly higher than those of controls (median, 1.5; range, 1–2; p < 0.001). ADAM–33 staining was increased in the mesenchymal cells of vessels of nasal polyps (median, 2; range, 1–3) compared with control tissues (median, 1.5; range, 1–2; p = 0.006). Although the staining scores of fibroblasts in nasal polyp specimens were also high (median, 3; range 1–3), there was no statistical significance when compared with controls (median 2; range, 1–3; p = 0.228). ADAM–33 immunostaining was not related with the presence of allergies, asthma, and aspirin intolerance (p > 0.05). Moreover, no relationship was found between increased expression of ADAM–33 and the stages of polyp or computerized tomography scores (p > 0.05). Conclusion This study suggests that the increased expression of ADAM-33 protein may have a role in the pathogenesis of NP.

Matrix metalloproteinase-9 promoter gene polymorphism (-1562C>T) in nasal polyposis.

Background Expression of matrix metalloproteinase (MMP)-9 increases in nasal polyp tissues. However, the impact of MMP-9 genotypes on the development of nasal polyposis (NP) is unknown. The aim of this study was to examine a potential association of MMP-9 promoter gene polymorphism with the development of NP. Methods A prospective and case–control study was performed on 93 patients with NP and 115 controls without sinonasal disease. Genotypes of MMP-9 (–1562C>T) were identified by restriction fragment length polymorphism analyses after polymerase chain reaction. Results The frequency of – 1562CT genotype of MMP-9 was significantly high in NP patients with aspirin-induced asthma (p = 0.014). Distribution of T allele was significantly high in NP patients with aspirin-induced asthma (p = 0.013). MMP-9 genotypes were not associated with gender or the presence of atopy. Conclusion In this study, MMP-9 – 1562CT genotype was associated with susceptibility to NP in aspirin-induced asthmatic patients. Because this report is a population-based study, further research should be performed on larger study subjects to reveal the precise role of MMP-9 promoter gene polymorphism in the development of NP.

Vestibular evoked myogenic potentials in Behcet's disease.

The aim of this study was to investigate vestibular evoked myogenic potentials (VEMPs) and their clinical significance in Behcet’s disease. Twenty-six patients with Behcet’s disease and 25 healthy volunteers were evaluated for pure tone audiometry, caloric response, and VEMPs. Sensorineural hearing loss was found in 53.8% of patients with Behcet’s disease, which was significantly higher than controls. Four patients had canal paresis, but no controls; this difference was not significant. Although VEMP recordings were elicited in all study subjects, mean p13 and n23 latencies were prolonged in Behcet’s patients compared with controls. Seven patients had delayed VEMP responses. There were no correlations regarding p13 values and age, duration or activity of disease, vertigo, or sensorineural hearing loss. The results of this preliminary study suggest an association between delayed VEMP responses and Behcet’s disease. Further research with large samples is needed to confirm that VEMP testing is useful to diagnose and follow vestibular dysfunction in Behcet’s disease.

Subjective pulsatile tinnitus associated with extensive pneumatization of temporal bone

Pulsatile tinnitus (PT), a rare otologic symptom, is frequently associated with identifiable and treatable causes. We report two cases of subjective PT due to extensive pneumatization of temporal bone around the internal carotid artery.

A founder TMIE mutation is a frequent cause of hearing loss in southeastern Anatolia

Using Affymetrix 10K arrays, we searched for regions of homozygosity in 51 Turkish families including at least three members with either congenital or prelingual autosomal recessive non‐syndromic sensorineural hearing loss (ARNSSNHL), and identified four families whose deafness mapped to the DFNB6 locus on 3p21 containing the TMIE gene. Mutation analysis revealed the p.R84W mutation in all four families. Screening of this mutation in 254 families with ARNSSNHL, without GJB2 mutations, revealed four additional affected families. A novel mutation was found in a non‐complementary marriage between a deaf couple who were homozygous for p.R84W and p.W57X, respectively with two affected children who were compound heterozygotes. Six of the TMIE families originated from southeastern Anatolia, making p.R84W a common cause of hearing loss in that region with a relative frequency of 10.3% (95% CI is 2.5–18.1%). The overall prevalence of the p.R84W mutation in ARNSSNHL in Turkey is 2.4% (95% CI is 0.7–4.0%). Genotyping of single‐nucleotide polymorphisms flanking the TMIE gene revealed a conserved haplotype, suggesting a single origin for p.R84W from a common ancestor 1250 years ago (95% CI is 650–2500 years). We conclude that p.R84W could be a common mutation in other Middle Eastern populations and should be included in mutation screening offered to individuals with ARNSSNHL.

Vestibular evoked myogenic potentials in preterm infants.

The goal of this study was to determine whether there was an association between perinatal risk factors of prematurity and vestibular evoked myogenic potentials (VEMPs). A prospective case-control trial was designed. Fifty preterm newborns (100 ears) with a gestational age <37 weeks were included. The control group consisted of 20 healthy term infants (40 ears). VEMP recordings were performed, and mean latencies of p13 were calculated in all study subjects. Multivariable logistic regression was used to investigate the influence of perinatal variables on abnormal VEMP responses. VEMPs were elicited in all term infants (40 ears). In preterm infants, the responses were normal in 71 ears, delayed in 24 and absent in 5. There was a significant difference between abnormal VEMP rates for preterm and term infants (p < 0.001). Asphyxia (OR = 13.985, p = 0.048) and time of VEMP test (OR = 0.865, p = 0.038) were related to abnormal VEMP responses. There was no association between delayed VEMPs and gestational age, birth weight, hemoglobin and bilirubin levels, phototherapy, intracranial hemorrhage, convulsions, sepsis, ototoxic drugs, transfusion, mechanical ventilation, retinopathy of prematurity, bronchopulmonary dysplasia and respiratory distress syndrome. These results suggest a delay in the maturation of VEMPs in premature infants. Asphyxia was the most important risk factor for abnormal VEMP responses in preterm infants.

Glycerol affects vestibular-evoked myogenic potentials and pure-tone hearing in patients with Ménière's disease.

Abstract Conclusion: The pure-tone audiometry results following glycerol administration indicated a positive effect on cochlear endolymphatic hydrops. Glycerol cervical vestibular-evoked myogenic potential (cVEMP) tests are a useful means of diagnosing saccular hydrops. There was no correlation between cVEMP and audiological results. Objective: To document the changes in pure-tone hearing outcomes and cVEMPs in patients with Ménière’s disease (MD) and 10 healthy volunteers before and after oral administration of glycerol. Methods: Twenty-nine study group subjects were chosen with complaints of vertigo. cVEMP testing and pure-tone hearing level testing were performed before and at 1, 2, and 3 h after administration of glycerol. Results: The means of the latencies, amplitudes, and difference ratio in 20 normal subject ears were determined. Based on these values, 9/29 MD-affected (MDA) ears (31%) had a unilaterally absent cVEMP. Compared with difference ratio values of the control groups there were significant differences in both latencies and amplitudes in MDA ears after glycerol administration. Before glycerol administration, there were significant differences between control and MDA ears on mean values of pure-tone hearing outcomes. Twenty patients in the MDA group showed significant pure-tone hearing outcomes after glycerol administration.