ABSTRACT
Objective To investigate the genetic causes of auditory neuropathy with optic atrophy in a family.Methods The proband's medical history and family history were inquired in detail,and relevant clinical examina-tions were performed to confirm the diagnosis of auditory neuropathy with optic atrophy,and the genetic pedigree of the family was drawn.Peripheral blood of proband(Ⅲ-7)was collected for whole exome sequencing,and the patho-genicity of the detected mutations were interpreted.Blood samples of proband's wife(Ⅲ-8),eldest daughter(Ⅳ-7),second daughter(Ⅳ-9)and son(Ⅳ-10)were tested for mutation sites by Sanger sequencing.Combined with clinical manifestations and examination results,the family was studied.Results The genetic pattern of this family was autosomal dominant.The proband showed decreased visual acuity at the age of 19,bilateral sensorineural deaf-ness at the age of 30,and decreased speech recognition rate.Among 20 members of the family of 5 generations,10(2 deceased)showed similar symptoms of hearing and visual impairment.Proband(Ⅲ-7),eldest daughter(Ⅳ-7)and son(Ⅳ-10)underwent relevant examination.Pure tone audiometry showed bilateral sensorineural deafness.ABR showed no response bilaterally.The 40 Hz AERP showed no response in both ears.OAE showed responses in some or all of the frequencies.No stapedial reflex was detected.The eye movement of Ⅲ-7 and Ⅳ-10 were reasona-ble in all directions,and color vision was normal.Ocular papilla atrophy was observed in different degrees in fundus examination.OCT showed thinning of optic disc nerve fibers in both eyes,and visual evoked potential showed pro-longed P100 wave peak.They were diagnosed as hereditary auditory neuropathy with optic atrophy.A mutation of the OPA1 gene c.1334G＞A(p.Arg445His,NM_015560.2)at a pathogenic locus on chromosome 3 was detected by whole exon detection in Ⅲ-7.The results of generation sequencing analysis showed that the OPA1 gene c.1334G＞A(p.Arg445His,NM_015560.2)mutation of chromosome 3 was also found in Ⅳ-7 and Ⅳ-10.Meanwhile,the gen-otypes of Ⅲ-8 and Ⅳ-9 were wild homozygous,that is,no mutation occurred.Conclusion The OPA1 c.1334G＞A(p.Arg445His,NM_015560.2)mutation site might be the pathogenic mutation in this family.
ABSTRACT
<p><b>OBJECTIVE</b>To investigate the role of TIM4 (T cell immunoglobulin and mucin domain molecule 4) in the pathogenesis of allergic rhinitis (AR) in mice, and to identify a novel therapeutic target for the treatment of AR.</p><p><b>METHODS</b>Twenty-one male BALB/C mice of clean grade were divided into three groups randomly (n = 7 per group) including control, AR and anti-TIM4 antibody treatment groups. In order to induce upper airway allergic inflammation, the mice from AR and anti-TIM4 antibody treatment groups were sensitized by intraperitoneal injection followed by intranasal challenge with ovalbumin. Before the ovalbumin challenge, a group of mice was treated with anti-TIM4 antibody. To assess the AR model, behavioral observation with immunological assessments and HE staining of nasal tissues were performed. The TIM4 expression in nasal tissues in different groups of mice were assessed by immunofluorescence and RT-PCR.SPSS18.0 software was used to analyze the data.</p><p><b>RESULTS</b>The AR model in mice was successfully established as shown by behavioral observation and immunological evaluation. RT-PCR assays showed the relative expression of TIM4 mRNA in nasal mucosa of AR, control and anti-TIM4 antibody treatment mice was 16.29 ± 3.80, 0.51 ± 0.60, 1.64 ± 0.98, respectively. There was statistically significant differences mong three group (F = 46.56, P < 0.05). The expression of TIM4 in AR group was significantly higher than those in control group (t = 8.650, P < 0.05) and anti-TIM4 group (t = 8.027, P < 0.05). The expression of TIM4 was significantly reduced in the anti-TIM4 antibody group, as well as control group (t = -0.623, P > 0.05). More expression of TIM4 was detected in local nasal tissues of AR mice, mainly located below the pseudostratified ciliated columnar epithelium.</p><p><b>CONCLUSIONS</b>TIM4 plays a crucial role in the pathogenesis of AR. Effective inhibition of TIM4 expression can partially reverse the pathological changes of AR.</p>