学科分类
/ 2
40 个结果
  • 简介:MitochondrialtRNAmutationsareoneoftheimportantcausesofbothsyndromicandnon-syndromicdeafness.Ofthose,syndromicdeafness-associatedtRNAmutationssuchastRNALeu(UUR)3243A>Gareoftenpresentinheteroplasmy,whilenon-syndromicdeafness-associatedtRNAmutationsincludingtRNASer(UCN)7445A>Gareofteninhomplasmyorinhighlevelsofheteroplasmy.ThesetRNAmutationsaretheprimarymutationsleadingtohearingloss.However,othertRNAmutationssuchastRNAThr15927G>AandtRNASer(UCN)7444G>AmayactinsynergywiththeprimarymitochondrialDNAmutations,modulatingthephenotypicmanifestationoftheprimarymitochondrialDNAmutations.ThesestRNAmutationscausestructuralandfunctionalalteration.AfailureintRNAmetabolismcausedbythesetRNAmutationsimpairedmitochondrialtranslationandrespiration,therebycausingmitochondrialdysfunctionsresponsiblefordeafness.Thesedataoffervaluableinformationfortheearlydiagnosis,managementandtreatmentofmaternallyinheriteddeafness.

  • 标签: 线粒体DNA突变 基因突变 TRNA 耳聋 线粒体蛋白 综合征
  • 简介:AbstractObjective:Biallelic mutations in the RecQ like helicase (RECQL) 4 gene, a guardian of the genome, cause Rothmund-Thomson syndrome type II (RTS-II). Two Chinese girls with mild-phenotype RTS-II mainly restricted to their skin are herein described.Methods:Blood specimens from two families with mild-phenotype RTS-II were collected. DNA isolation, RNA isolation and complementary DNA synthesis, and next-generation sequencing using a multi-gene panel were applied to verify the underlying pathogenic variants in the causative RECQL4 gene.Results:We analyzed two patients with mild phenotypes. One patient had an unreported paternal c.2885+1G>A alteration in intervening sequence 16 and the previously reported maternal exon 14 c.2272C>T (p.R758X), both resulting in premature termination codons. The other patient carried two novel alterations, c.2886-1G>A and c.2752G>T (p.E918X). Complementary DNA sequencing showed that different splice-site mutations within the same intron could lead to completely different splicing modes.Conclusion:We identified three novel pathogenic RECQL4 variants in two patients with RTS, thus expanding the mutational spectrum of RTS-II. We also explored their pathogenic effect by transcripts analysis to address genotype-phenotype correlations.

  • 标签: exon-skipping genodermatosis RECQL4 variants Rothmund-Thomson syndrome splice-site mutation
  • 简介:Themitochondrial12SrRNAhasbeenshowntobethehotspotformutationsassociatedwithbothaminoglycoside-inducedandnon-syndromichearingloss.Ofallthemutations,thehomoplasmicA1555GandC1494Tmutationsatahighlyconserveddecodingregioninthe12SrRNAhavebeenassociatedwithaminoglycoside-inducedandnon-syndromichearinglossinmanyfamiliesworldwide.TheA1555GorC1494Tmutationisexpectedtoformnovel1494C-G1555or1494U-A1555base-pairatthehighlyconservedA-siteof12SrRNA.ThesetransitionsmakethesecondarystructureofthisRNAmorecloselyresemblethecorrespondingregionofbacterial16SrRNA.Thus,thenewU-AorG-Cpairin12SrRNAcreatedbytheC1494TorA1555Gtransitionfacilitatesthebindingofaminoglycosides,therebyaccountingforthefactthattheexposuretoaminoglycosidescaninduceorworsenhearinglossinindividualscarryingthesemutations.Furthermore,thegrowthdefectandimpairmentofmitochondrialtranslationwereobservedincelllinescarryingtheA1555GorC1494Tmutationinthepresenceofhighconcentrationofaminoglycosides.Inaddition,nuclearmodifiergenesandmitochondrialhaplotypesmodulatethephenotypicmanifestationoftheA1555GandC1494Tmutations.TheseobservationsprovidethedirectgeneticandbiochemicalevidencesthattheA1555GorC1494TmutationisapathogenicmtDNAmutationassociatedwithaminoglycoside-inducedandnonsyndromichearingloss.Therefore,thesedatahavebeenprovidingvaluableinformationandtechnologytopredictwhichindividualsareatriskforototoxicity,toimprovethesafetyofaminoglycosideantibiotictherapy,andeventuallytodecreasetheincidenceofdeafness.

  • 标签: NONSYNDROMIC HEARING loss SECONDARY structure cell
  • 简介:MutationsinmitochondrialtRNAgeneshavebeenshowntobeassociatedwithmaternallyinheritedsyn-dromicandnon-syndromicdeafness.Amongthose,mutationssuchastRNALeu(UUR)3243A>Gassociatedwithsyndromicdeafnessareoftenpresentinheteroplasmy,andthenon-syndromicdeafness-associatedtRNAmu-tationsincludingtRNASer(UCN)7445A>Gareofteninhomoplasmyorinhighlevelsofheteroplasmy.ThesetRNAmutationsaretheprimaryfactorsunderlyingthedevelopmentofhearingloss.However,othertRNAmutationssuchastRNAThr15927G>AandtRNASer(UCN)7444G>Aareinsufficienttoproduceadeafnessphe-notype,butalwaysactinsynergywiththeprimarymitochondrialDNAmutations,andcanmodulatetheirphenotypicmanifestation.ThesetRNAmutationsmayalterthestructureandfunctionofthecorrespondingmitochondrialtRNAsandcausefailuresintRNAsmetabolism.Thereby,theimpairmentofmitochondrialproteinsynthesisandsubsequentdefectsinrespirationcausedbythesetRNAmutations,resultsinmitochon-drialdysfunctionsandeventuallyleadstothedevelopmentofhearingloss.Here,wesummarizedthedeaf-ness-associatedmitochondrialtRNAmutationsanddiscussedthepathophysiologyofthesemitochondrialtRNAmutations,andwehopethesedatawillprovideafoundationfortheearlydiagnosis,management,andtreatmentofmaternallyinheriteddeafness.

  • 标签:
  • 简介:

  • 标签:
  • 简介:TheGJB2gene(connexin26)hasbeenshowntoberesponsibleforDFNB1andDFNA3.WescreenedtheGJB2genein488patientswithprelingualdeafness(Group1),124withpostlingualdeafness(Group2),and117normalhearingsubjects(Group3).Wefoundthat,inGroup1,65patients(13.32%)werehomozygotesorcompoundheterozygotesand51patients(10.45%)carriedasinglepathogenicmutation.The235delCmutationwasthemostfrequentmutation,accountingfor73.22%oftheknownpathogenicallelesinGroup1.NohomozygotesorcompoundheterozygotesweredetectedinGroup2orGroup3.Somepostlingualdeafpatients(2.42%)andnormalhearingsubjects(4.27%)were235delCcarriers.Ourpreliminarydataindicatethat235delC,themostfrequentmutationidentifiedinthisstudy,isamajorcauseforprelingualdeafness.

  • 标签:
  • 简介:Aminoglycosides(AmAn)arewidelyusedfortheirgreatefficiencyagainstgram-negativebacterialinfections.However,theycanalsoinduceototoxichearingloss,whichhasaffectedmillionsofpeoplearoundtheworld.Aspreviouslyreported,individualsbearingmitochondrialDNAmutationsinthe12SrRNAgene,suchasm.1555A>Gandm.1494C>T,aremorepronetoAmAn-inducedototoxicity.Thesemutationscausehumanmitochondrialribosomestomorecloselyresemblebacterialribosomesandenableastrongeraminoglycosideinteraction.Consequently,exposuretoAmAncaninduceorworsenhearinglossintheseindividuals.Furthermore,awiderangeofseverityandpenetranceofhearinglosswasobservedamongfamiliescarryingthesemutations.StudieshaverevealedthatthesemitochondriamutationsaretheprimarymolecularmechanismofgeneticsusceptibilitytoAmAnototoxicity,thoughnuclearmodifiergenesandmitochondrialhaplotypesareknowntomodulatethephenotypicmanifestation.

  • 标签: AMINOGLYCOSIDES OTOTOXICITY Genetic SUSCEPTIBILITY MITOCHONDRIAL DNA
  • 简介:在源于mitochondrial机能障碍的氧化phosphorylation的改变长被假设了涉及tumorigenesis。线粒体最近被显示了在调整规划房间死亡和房间增长起一个重要作用。而且,mitochondrialDNA(mtDNA)变化在各种各样的癌症房间被发现了。然而,在tumorigenesis的这些mtDNA变化的角色仍然保持大部分未知。这评论集中于基本mitochondrial遗传,mtDNA变化和与癌症联系的结果的mitochondrial机能障碍。潜在的分子的机制,调停从mtDNA变化的致病和到tumorigenesis的mitochondrial机能障碍也被讨论。

  • 标签: 线粒体DNA突变 功能障碍 程序性细胞死亡 分子机制 氧化磷酸化 MTDNA
  • 简介:AbstractImportance:CHD2 is a member of the chromodomain helicase DNA-binding (CHD) family of proteins, which have important roles in the regulation of gene expression. Dysregulation of this protein may lead to various disorders.Objective:To delineate the genotypes and phenotypes of CHD2-related epilepsy.Methods:We analyzed the medical history, magnetic resonance imaging findings, and video-electroencephalogram recordings of 17 patients with CHD2 mutations in the Neurology Department of Beijing Children’s Hospital from June 2016 to June 2021.Results:Age at seizure onset ranged from 6 months to 10 years; the median age at onset was 4 years. Generalized tonic-clonic, myoclonic, eyelid myoclonic, atonic, atypical absence, myoclonic-atonic, and spasm seizures were observed. Ten of the 17 patients had multiple types of seizures. One patient exhibited photosensitivity epilepsy and one patient exhibited grid image-induced visual reflex epilepsy. Developmental disability was present in 14 patients, while autism features were present in five patients. Sixteen patients had de novo mutations of CHD2; one patient had an inherited variant. Eleven mutations were novel. One patient had two mutations; that patient exhibited development delay and refractory epilepsy. Seizures were controlled in eight patients, improved in seven patients, and resistant to treatment in two patients.Interpretation:Phenotype severity in patients with CHD2 variants ranged from drug-responsive seizures to severe epileptic encephalopathy. Most patients exhibited developmental disorders.

  • 标签: CHD2 Epilepsy Developmental disability Phenotype Seizure
  • 简介:

  • 标签:
  • 简介:

  • 标签:
  • 简介:

  • 标签:
  • 简介:BackgroundChronicotitismedia(COM)isasignificantclinicalproblem.UnderstandingthemechanismsofCOMiscriticalforitscontrolandtreatment.However,littleisknownoftheprocessesleadingtoCOMasaresultoflackofanimalmodelsofN-ethyl-N-nitrosourea(ENU)inducedmutationsinotitismediawitheffusion(OME).MethodsOtoscopyandauditorybrainresponse(ABR)evaluationwerecarriedoutundersedationinNmf391nmf/nmfmiceof2,4,6and8monthsofage.Themicewerekilledforstudyofmiddleandinnerearpathology.ResultsTympanicmembranevisualizationandABRthresholdsin1-to8-month-oldNmf391nmf/nmfmiceshowedspontaneousOMEandinnereardiseasesinapproximately100%oftheanimals.ThesignificantelevationofABRthresholdssuggestedasensorineuralcomponentinhearinglossinadditiontotheconductiveloss.Middleandinnerearhistologyshowedvariousdegreesofouterhaircellslossandmiddleearinflammationinallthemice,butnoinflammationcellsintheinnerear.TheABRthresholdat32kHzwassignificantlyelevated.ConclusionsThisstudyshowshistopathologicchangesintheNmf391nmf/nmfmousemodelofCOMwitheffusionthathavenotbeenreportedinhumanCOM.ThisENUinducedmutationmodelofCOMwillbevaluableforthecharacterizationofmiddleearinflammationandinnereardiseaseprocessesthatareinducedbymiddleearinfections.WeproposethatCOMwitheffusioninthisENUinducedmutationmodelisthecauseofthecochleahaircellsdamage.

  • 标签:
  • 简介:AbstractWe analyzed variations in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome during a flight-related cluster outbreak of coronavirus disease 2019 (COVID-19) in Shenzhen, China, to explore the characteristics of SARS-CoV-2 transmission and intra-host single nucleotide variations (iSNVs) in a confined space. Thirty-three patients with COVID-19 were sampled, and 14 were resampled 3-31 days later. All 47 nasopharyngeal swabs were deep-sequenced. iSNVs and similarities in the consensus genome sequence were analyzed. Three SARS-CoV-2 variants of concern, Delta (n = 31), Beta (n = 1), and C.1.2 (n = 1), were detected among the 33 patients. The viral genome sequences from 30 Delta-positive patients had similar SNVs; 14 of these patients provided two successive samples. Overall, the 47 sequenced genomes contained 164 iSNVs. Of the 14 paired (successive) samples, the second samples (T2) contained more iSNVs (median: 3; 95% confidence interval [95% CI]: 2.77-10.22) than did the first samples (T1; median: 2; 95% CI: 1.63-3.74; Wilcoxon test, P = 0.021). 38 iSNVs were detected in T1 samples, and only seven were also detectable in T2 samples. Notably, T2 samples from two of the 14 paired samples had additional mutations than the T1 samples. The iSNVs of the SARS-CoV-2 genome exhibited rapid dynamic changes during a flight-related cluster outbreak event. Intra-host diversity increased gradually with time, and new site mutations occurred in vivo without a population transmission bottleneck. Therefore, we could not determine the generational relationship from the mutation site changes alone.

  • 标签: SARS-CoV-2 Cluster epidemic Intra-host single nucleotide variation
  • 简介:AbstractBackground:Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers without effective therapy. To explore potential molecular targets in ESCC, we quantified the mutation spectrum and explored the relationship between gene mutation and clinicopathological characteristics and programmed death-ligand 1 (PD-L1) expression.Methods:Between 2015 and 2019, 29 surgically resected ESCC tissues and adjacent normal tissues from the Fourth Hospital of Hebei Medical University were subjected to targeted next-generation sequencing. The expression levels of PD-L1 were detected by immunohistochemistry. Mutational signatures were extracted from the mutation count matrix by using non-negative matrix factorization. The relationship between detected genomic alterations and clinicopathological characteristics and PD-L1 expression was estimated by Spearman rank correlation analysis.Results:The most frequently mutated gene was TP53 (96.6%, 28/29), followed by NOTCH1 (27.6%, 8/29), EP300 (17.2%, 5/29), and KMT2C (17.2%, 5/29). The most frequently copy number amplified and deleted genes were CCND1/FGF3/FGF4/FGF19 (41.4%, 12/29) and CDKN2A/2B (10.3%, 3/29). By quantifying the contribution of the mutational signatures to the mutation spectrum, we found that the contribution of signature 1, signature 2, signature 10, signature 12, signature 13, and signature 17 was relatively high. Further analysis revealed genetic variants associated with cell cycle, chromatin modification, Notch, and Janus kinase-signal transducer and activator of transcription signaling pathways, which may be key pathways in the development and progression of ESCC. Evaluation of PD-L1 expression in samples showed that 13.8% (4/29) of samples had tumor proportion score ≥1%. 17.2% (5/29) of patients had tumor mutation burden (TMB) above 10 mut/Mb. All samples exhibited microsatellite stability. TMB was significantly associated with lymph node metastasis (r = 0.468, P = 0.010), but not significantly associated with PD-L1 expression (r = 0.246, P = 0.198). There was no significant correlation between PD-L1 expression and detected gene mutations (all P > 0.05).Conclusion:Our research initially constructed gene mutation profile related to surgically resected ESCC in high-incidence areas to explore the mechanism underlying ESCC development and potential therapeutic targets.

  • 标签: Esophageal squamous cell carcinoma Next-generation sequencing Mutational signature Programmed death-ligand 1
  • 简介:Objective:ToanalyzetypeⅡtopoisomerasegenesinclinicalisolatesoffluoroquinolone-resistantMycoplasmahominis.Methods:EightisolatesofM.hominiscrossresistantto6fluoroquinoloneswereselectedfrom103clinicalstrainsofM.hominisusingabrothmicrodilutionmethod.TypeIItopoisomerasegeneswereamplifiedbyPCRanddirectlysequenced.Nucleotidesequenceswerecomparedtosequencesfromasusceptiblestrain(M.hominisPG2I).Results:MICsofresistantMhisolateswere4-to512-foldhigherthanMICsfromthesusceptiblereferencestrain.SequencecomparisonrevealedaCtoTchangeat113ntingyrAQRDRledtothesubstitutionofSer83byLeucineandnoaminoacidchangeingyrB.AchangeofGtoTat134ntinparCQRDRledtothesubstitutionofSer80byIsoleucineandaGtoAchangeat70ntinparEQRDRledtothesubstitutionofAsparticacidbyAsparagine.Conclusion:TheseresultssuggestthataCtoTchangeatll3ntingyrA,aGtoTchangeat134ntinparCandaGtoAchangeat70ntinpatrEareassociatedwithfluoroquinoloneresistanceofM.hominis.

  • 标签: 支原体感染 基因突变 临床研究 PCR 聚合酶链反应 核酸
  • 简介:ObjectiveToinvestigateGJB2mutationprevalencesintheUigurandHanethnicgroupsinXinjiang,China,anddeterminetherelationshipbetweenethnicityandGJB2genemutations.MethodsInformationregardingethnicityofpatients'familieswasobtainedthroughmedicalrecordsreviewand/orpatientinterview.Bloodsampleswerecollectedfrom61Uigursand66Hansfordirectsequencingofthecodingregionandintron/exonboundariesoftheGBJ2gene.ResultsCarrierfrequencyofGJB2mutationswassimilarbetweentheUigurandHansubjects.TheGJB235delGmutationwasseenonlyinUigurpatientswithhearingloss,whereasthe235delCmutationwasidentifiedinbothUigurandHanpatients.TheallelicFrequencyof35delGmutationwas7.4%(9/122)inUigurdeafstudents,butnoneinHandeafstudents(0/128)andUigurcontrols(0/196).TheallelicfrequencyofGJB2235delCmutationinUigurandHandeafstudentswas5.7%and9.8%,andthatof299-300delATmutationwas0.8%and5.5%,respectively.V27IandE114Gwerethemostfrequenttypesofpolymorphism.ConclusionWefoundanAsian-specificGJB2diversityamongUigurs,andcomparableGJB2contributiontodeafnessinUigurandHanpatients.Thehighcarrierfrequencyof35delGinUigurs(11.5%)isprobablydefinedbygenedrift/foundereffectinaparticulargroup.EventhoughGJB2mutationshavebeenwidelyreportedintheliterature,thisdiscussionrepresentsthefirstreportofGJB2mutationsinChinesemulti-ethnicpopulations.

  • 标签: