Auditory neuropathy spectrum disorder(ANSD)represents a variety of sensorineural deafness conditions characterized by abnormal inner hair cells and/or auditory nerve function,but with the preservation of outer hair ce...Auditory neuropathy spectrum disorder(ANSD)represents a variety of sensorineural deafness conditions characterized by abnormal inner hair cells and/or auditory nerve function,but with the preservation of outer hair cell function.ANSD represents up to 15%of individuals with hearing impairments.Through mutation screening,bioinformatic analysis and expression studies,we have previously identified several apoptosis-inducing factor(AIF)mitochondria-associated 1(AIFM1)variants in ANSD families and in some other sporadic cases.Here,to elucidate the pathogenic mechanisms underlying each AIFM1 variant,we generated AIF-null cells using the clustered regularly interspersed short palindromic repeats(CRISPR)/CRISPR-associated protein 9(Cas9)system and constructed AIF-wild type(WT)and AIF-mutant(mut)(p.T260A,p.R422W,and p.R451Q)stable transfection cell lines.We then analyzed AIF structure,coenzyme-binding affinity,apoptosis,and other aspects.Results revealed that these variants resulted in impaired dimerization,compromising AIF function.The reduction reaction of AIF variants had proceeded slower than that of AIF-WT.The average levels of AIF dimerization in AIF variant cells were only 34.5%-49.7%of that of AIF-WT cells,resulting in caspase-independent apoptosis.The average percentage of apoptotic cells in the variants was 12.3%-17.9%,which was significantly higher than that(6.9%-7.4%)in controls.However,nicotinamide adenine dinucleotide(NADH)treatment promoted the reduction of apoptosis by rescuing AIF dimerization in AIF variant cells.Our findings show that the impairment of AIF dimerization by AIFM1 variants causes apoptosis contributing to ANSD,and introduce NADH as a potential drug for ANSD treatment.Our results help elucidate the mechanisms of ANSD and may lead to the provision of novel therapies.展开更多
Dear Editor.Meniere's disease(MD,MIM 156000),a chronic clinical illness affecting the inner ear,presents as episodes of spontaneous vertigo,fluctuating sensorineural hearing loss,tinnitus,and aural fullness.Endoly...Dear Editor.Meniere's disease(MD,MIM 156000),a chronic clinical illness affecting the inner ear,presents as episodes of spontaneous vertigo,fluctuating sensorineural hearing loss,tinnitus,and aural fullness.Endolymphatic hydrops in the cochlear duct and vestibular organs is considered the underlying histopathologic characteristic of MD.Most MD cases are sporadic(sporadic Meniere's disease,SMD),and approximately 4%-20%of patients with MD have a familial history.展开更多
Auditory neuropathy spectrum disorder is a unique group of hearing dysfunctions characterized by preserved outer hair cell function and abnormal neural conduction of the auditory pathway. However, the pathogenic mecha...Auditory neuropathy spectrum disorder is a unique group of hearing dysfunctions characterized by preserved outer hair cell function and abnormal neural conduction of the auditory pathway. However, the pathogenic mechanism underlying this disorder is not clear. We therefore performed a systematic review of genetic mouse models with different gene mutations to provide a valuable tool for better understanding of the process and the possible molecular mechanisms. Of the 18 articles retrieved, nine met the required criteria. All biochemical, histological, and electrophysiological results were recorded for each of the mouse models, as was the transgenic technology. This review provides a summary of different mouse models that may play an important role in the diagnosis and management of auditory neuropathy spectrum disorder in the future.展开更多
Dear Editor,Actins are a family of essential cytoskeletal proteins involved in nearly all cellular processes(Lambrechts et al.,2004).Of the six human genes that encode actins,only ACTG1and ACTB are ubiquitously expres...Dear Editor,Actins are a family of essential cytoskeletal proteins involved in nearly all cellular processes(Lambrechts et al.,2004).Of the six human genes that encode actins,only ACTG1and ACTB are ubiquitously expressed.ACTG1(OMIM#604717),which is linked to the DFNA20/26 locus。展开更多
Preimplantation genetic diagnosis(PGD)uses molecular biological techniques to genetically diagnose embryos beforein vitro fertilization.The information obtained through PGD can help clinicians select healthy embryos f...Preimplantation genetic diagnosis(PGD)uses molecular biological techniques to genetically diagnose embryos beforein vitro fertilization.The information obtained through PGD can help clinicians select healthy embryos for implantation,prevent the transmission of inherited diseases and help affected families have healthy children.This paper reviews the development of PGD technology,the history of its application to hereditary hearing loss,and the general process of how PGD is applied to screen for hereditary hearing loss.The aim of this review is to demonstrate the reliability of PGD in the primary prevention of hereditary hearing loss,assist clinicians in counseling patients at risk of transmitting an inherited disease,and explore the journey from PGD toin vitro fertilization.Given that the application of PGD technology to hereditary hearing loss varies in different countries and regions,there is still a long way to go before PGD is routinely applied for the primary prevention of hereditary hearing loss.展开更多
KCNQ4 gene mutation can lead to deafness non-syndromic autosomal dominant 2A,which is a type of autosomal dominant non-syndromic hearing loss.Deafness non-syndromic autosomal dominant 2A patients with KCNQ4 gene mutat...KCNQ4 gene mutation can lead to deafness non-syndromic autosomal dominant 2A,which is a type of autosomal dominant non-syndromic hearing loss.Deafness non-syndromic autosomal dominant 2A patients with KCNQ4 gene mutation usually present with symmetrical,delayed,progressive high-frequency-affected hearing loss,which eventually can involve all frequencies.In this article,we comprehensively reviewed the research on the role and function of KCNQ4 gene in genetic hearing loss.We discussed the pathological and physiological mechanisms of KCNQ4 gene and the related clinical phenotypes of KCNQ4 gene mutations.We also reviewed the latest developments in the treatment of KCNQ4 gene mutation-related genetic hearing loss,including selective potassium channel activation drugs and gene therapy.展开更多
Hereditary hearing loss is one of the most common neurosensory defects in humans. Approximately 70% of cases are nonsyndromic and could be inherited in autosomal domi- nant, autosomal recessive, mitochondrial, X-linke...Hereditary hearing loss is one of the most common neurosensory defects in humans. Approximately 70% of cases are nonsyndromic and could be inherited in autosomal domi- nant, autosomal recessive, mitochondrial, X-linked, and Y-linked manners (Wang et al., 2004; Alford, 2011). The autosomal dominant type, comprising 15%-20% of non- syndromic hearing loss, is monogenic and genetically heterogeneous. Since the first dominant deafness locus (DFNA 1) was identified in 1992, a total of 64 DFNA loci have been mapped (DFNA1-DFNA64),展开更多
基金the National Natural Science Foundation of China(Nos.32070584,81830028,31771398,82222016,and 8207040100)the Zhejiang Provincial Natural Science Foundation of China(No.LZ19C060001)the Fundamental Research Funds for the Central Universities(No.2019QNA6001)。
文摘Auditory neuropathy spectrum disorder(ANSD)represents a variety of sensorineural deafness conditions characterized by abnormal inner hair cells and/or auditory nerve function,but with the preservation of outer hair cell function.ANSD represents up to 15%of individuals with hearing impairments.Through mutation screening,bioinformatic analysis and expression studies,we have previously identified several apoptosis-inducing factor(AIF)mitochondria-associated 1(AIFM1)variants in ANSD families and in some other sporadic cases.Here,to elucidate the pathogenic mechanisms underlying each AIFM1 variant,we generated AIF-null cells using the clustered regularly interspersed short palindromic repeats(CRISPR)/CRISPR-associated protein 9(Cas9)system and constructed AIF-wild type(WT)and AIF-mutant(mut)(p.T260A,p.R422W,and p.R451Q)stable transfection cell lines.We then analyzed AIF structure,coenzyme-binding affinity,apoptosis,and other aspects.Results revealed that these variants resulted in impaired dimerization,compromising AIF function.The reduction reaction of AIF variants had proceeded slower than that of AIF-WT.The average levels of AIF dimerization in AIF variant cells were only 34.5%-49.7%of that of AIF-WT cells,resulting in caspase-independent apoptosis.The average percentage of apoptotic cells in the variants was 12.3%-17.9%,which was significantly higher than that(6.9%-7.4%)in controls.However,nicotinamide adenine dinucleotide(NADH)treatment promoted the reduction of apoptosis by rescuing AIF dimerization in AIF variant cells.Our findings show that the impairment of AIF dimerization by AIFM1 variants causes apoptosis contributing to ANSD,and introduce NADH as a potential drug for ANSD treatment.Our results help elucidate the mechanisms of ANSD and may lead to the provision of novel therapies.
基金This work was financially supported by the National Institute of Advanced Industrial Science and Technology(AIST),Jiangsu University(4023000046)Shenzhen Key Laboratory of Micro/Nano-Porous Functional Materials(SKLPM)(ZDSYS20210709112802010)+2 种基金China Postdoctoral Science Foundation(2022TQ0126 and 2022M721375)Guangdong Grants(2021ZT09C064)the National Key Research and Development Project(2022YFA1503900).
基金supported by grants from the National Key Basic Research Program of China (2014CB943001)the National Natural Science Foundation of China (81530032 & 81830028)
文摘Dear Editor.Meniere's disease(MD,MIM 156000),a chronic clinical illness affecting the inner ear,presents as episodes of spontaneous vertigo,fluctuating sensorineural hearing loss,tinnitus,and aural fullness.Endolymphatic hydrops in the cochlear duct and vestibular organs is considered the underlying histopathologic characteristic of MD.Most MD cases are sporadic(sporadic Meniere's disease,SMD),and approximately 4%-20%of patients with MD have a familial history.
基金supported by the National Key Basic Research Program of China (2014CB943001)the National Natural Science Foundation of China (81120108009, 81530032)
文摘Auditory neuropathy spectrum disorder is a unique group of hearing dysfunctions characterized by preserved outer hair cell function and abnormal neural conduction of the auditory pathway. However, the pathogenic mechanism underlying this disorder is not clear. We therefore performed a systematic review of genetic mouse models with different gene mutations to provide a valuable tool for better understanding of the process and the possible molecular mechanisms. Of the 18 articles retrieved, nine met the required criteria. All biochemical, histological, and electrophysiological results were recorded for each of the mouse models, as was the transgenic technology. This review provides a summary of different mouse models that may play an important role in the diagnosis and management of auditory neuropathy spectrum disorder in the future.
基金supported by the National Natural Science Foundation of China(81530032)the National Key Basic Research Program of China(2014CB943001)
文摘Dear Editor,Actins are a family of essential cytoskeletal proteins involved in nearly all cellular processes(Lambrechts et al.,2004).Of the six human genes that encode actins,only ACTG1and ACTB are ubiquitously expressed.ACTG1(OMIM#604717),which is linked to the DFNA20/26 locus。
基金supported by the grants of the National Natural Science Foundation of China(Major Project No.81830028,Youths Program Nos.81900951 and 81900950)Beijing Municipal Natural Science Foundation Youth Projects(No.7204312)National Key Research and Development Project(No.2020YFC2005201)。
文摘Preimplantation genetic diagnosis(PGD)uses molecular biological techniques to genetically diagnose embryos beforein vitro fertilization.The information obtained through PGD can help clinicians select healthy embryos for implantation,prevent the transmission of inherited diseases and help affected families have healthy children.This paper reviews the development of PGD technology,the history of its application to hereditary hearing loss,and the general process of how PGD is applied to screen for hereditary hearing loss.The aim of this review is to demonstrate the reliability of PGD in the primary prevention of hereditary hearing loss,assist clinicians in counseling patients at risk of transmitting an inherited disease,and explore the journey from PGD toin vitro fertilization.Given that the application of PGD technology to hereditary hearing loss varies in different countries and regions,there is still a long way to go before PGD is routinely applied for the primary prevention of hereditary hearing loss.
基金supported by the grants of the National Natural Science Foundation of China(Major Project No.81830028,Youths Program Nos.81900950 and 81900951).
文摘KCNQ4 gene mutation can lead to deafness non-syndromic autosomal dominant 2A,which is a type of autosomal dominant non-syndromic hearing loss.Deafness non-syndromic autosomal dominant 2A patients with KCNQ4 gene mutation usually present with symmetrical,delayed,progressive high-frequency-affected hearing loss,which eventually can involve all frequencies.In this article,we comprehensively reviewed the research on the role and function of KCNQ4 gene in genetic hearing loss.We discussed the pathological and physiological mechanisms of KCNQ4 gene and the related clinical phenotypes of KCNQ4 gene mutations.We also reviewed the latest developments in the treatment of KCNQ4 gene mutation-related genetic hearing loss,including selective potassium channel activation drugs and gene therapy.
基金supported by the grants from the National Natural Science Foundation of China,key project(No.30830104) and major project(No.81120108009)
文摘Hereditary hearing loss is one of the most common neurosensory defects in humans. Approximately 70% of cases are nonsyndromic and could be inherited in autosomal domi- nant, autosomal recessive, mitochondrial, X-linked, and Y-linked manners (Wang et al., 2004; Alford, 2011). The autosomal dominant type, comprising 15%-20% of non- syndromic hearing loss, is monogenic and genetically heterogeneous. Since the first dominant deafness locus (DFNA 1) was identified in 1992, a total of 64 DFNA loci have been mapped (DFNA1-DFNA64),