AIFM1 variants associated with auditory neuropathy spectrum disorder cause apoptosis due to impaired apoptosis-inducing factor dimerization

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.

MOF衍生的磷化钴纳米纤维用于电催化氧析出和氢析出反应

高性能催化剂的开发和利用是能源领域的研究热点,其中制备具有高活性面积的一维纳米催化剂是目前的难点.本研究以金属有机框架(MOF)复合纤维为前驱体,通过热处理-磷化过程制备了具有氧析出(OER)和氢析出(HER)双功能特性的CoP纳米纤维.该MOF衍生策略也可以用来制备其他一维纳米材料,如Co_(3)O_(4)纳米纤维、Co/C纤维和CoP/C复合纤维.研究表明,CoP纳米纤维的直径约100 nm,长度可达几微米,具有较高的活性面积.通过Cu掺杂改性可以提高CoP纳米纤维的催化活性,碱性条件下测得其对OER和HER的过电位分别为330和170 mV,可与商业的贵金属催化剂相媲美.该工作也为一维双功能电极催化剂的制备及功能化提供了研究基础.

Molecular genetic studies of familial Meniere’s disease

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.

Understanding auditory neuropathy spectrum disorder： a system- atic review in transgenic mouse models

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.

A novel de novo mutation of ACTG1 in two sporadic non-syndromic hearing loss cases

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。

Preimplantation genetic diagnosis of hereditary hearing loss:a narrative review

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.

Progression of KCNQ4 related genetic hearing loss:a narrative review

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.

Clue to a New Deafness Gene:A Large Chinese Nonsyndromic Hearing Loss Family Linked to DFNA4

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）,