RESUMO
Auditory neuropathy is a rare form of deafness characterized by an absent or abnormal auditory brainstem response with preservation of outer hair cell function. We have identified Diaphanous homolog 3 (DIAPH3) as the gene responsible for autosomal dominant nonsyndromic auditory neuropathy (AUNA1), which we previously mapped to chromosome 13q21-q24. Genotyping of additional family members narrowed the interval to an 11-Mb, 3.28-cM gene-poor region containing only four genes, including DIAPH3. DNA sequencing of DIAPH3 revealed a c.-172G>A, g. 48G>A mutation in a highly conserved region of the 5' UTR. The c.-172G>A mutation occurs within a GC box sequence element and was not found in 379 controls. Using genome-wide expression arrays and quantitative RT-PCR, we demonstrate a 2- to 3-fold overexpression of DIAPH3 mRNA in lymphoblastoid cell lines from affected individuals. Likewise, a significant increase (approximately 1.5-fold) in DIAPH3 protein was found by quantitative immunoblotting of lysates from lymphoblastoid cell lines derived from affected individuals in comparison with controls. In addition, the c.-172G>A mutation is sufficient to drive overexpression of a luciferase reporter. Finally, the expression of a constitutively active form of diaphanous protein in the auditory organ of Drosophila melanogaster recapitulates the phenotype of impaired response to sound. To date, only two genes, the otoferlin gene OTOF and the pejvakin gene PJVK, are known to underlie nonsyndromic auditory neuropathy. Genetic testing for DIAPH3 may be useful for individuals with recessive as well as dominant inheritance of nonsyndromic auditory neuropathy.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Surdez/genética , Drosophila melanogaster/genética , Perda Auditiva Neurossensorial/genética , Regiões 5' não Traduzidas/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Sequência de Bases , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proteínas de Transporte/fisiologia , Linhagem Celular Transformada , Surdez/metabolismo , Surdez/patologia , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/fisiologia , Drosophila melanogaster/metabolismo , Drosophila melanogaster/fisiologia , Potenciais Evocados/fisiologia , Feminino , Forminas , Perfilação da Expressão Gênica , Perda Auditiva Neurossensorial/metabolismo , Perda Auditiva Neurossensorial/patologia , Humanos , Immunoblotting , Luciferases/genética , Luciferases/metabolismo , Masculino , Camundongos , Dados de Sequência Molecular , Células NIH 3T3 , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , Mutação Puntual , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Homologia de Sequência do Ácido Nucleico , SomRESUMO
Objective: Managing type 1 diabetes is stressful. Stress physiology influences glucose metabolism. Continuous glucose monitors allow us to track glucose variability in the real-world environment. Managing stress and cultivating resiliency should improve diabetes management and reduce glucose variability. Research Design and Methods: The study was designed as a randomized prospective cohort pre-post study with wait time control. Participants were adult type 1 diabetes patients who used a continuous glucose monitor and recruited from an academic endocrinology practice. The intervention was the Stress Management and Resiliency Training (SMART) program conducted over 8 sessions over web-based video conference software. The main outcome measures were Glucose variability, the Diabetes Self-Management questionnaire (DSMQ),Short-Form Six-Dimension (SF-6D), and the Connor-Davidson Resiliency (CD-RSIC) instrument. Results: There was statistically significant improvement in participants DSMQ and CD RISC scores though the SF-6D did not change. Participants under age 50 years-old showed a statistically significant reduction in average glucose (p = .03) and Glucose Management Index (GMI) (p = .02). Participants also had reduced percentage of time high and increased time in range though this did not reach statistical significance. The participants found doing the intervention online acceptable if not always ideal. Conclusions: An 8-session stress management and resiliency training program reduced diabetes related stress and improved resiliency and reduced average blood glucose and GMI in those under 50 years-old. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT04944264.