Universities should take undergraduate education as the fundamental connotation of the times,and we will return to common sense,duty,original aspiration and dream,which is the basic principle of the reform and develop...Universities should take undergraduate education as the fundamental connotation of the times,and we will return to common sense,duty,original aspiration and dream,which is the basic principle of the reform and development of colleges and universities. Speeding up the construction of high-level undergraduate education and improving the ability of talent training in an all-round way,eliminating nonsensical courses and creating first-rate courses has become one of the important tasks of teaching in higher education. Starting from the standard of first-rate courses,this paper deeply analyzes the reasons for the prevalence of nonsensical courses,and expounds some ways to control nonsensical courses and create first-rate courses.展开更多
High-molecular-weight glutenin subunits(HMW-GSs) are the most critical grain storage proteins that determine the unique processing qualities of wheat. Although it is a part of the superior HMW-GS pair(Dx5+Dy10), the c...High-molecular-weight glutenin subunits(HMW-GSs) are the most critical grain storage proteins that determine the unique processing qualities of wheat. Although it is a part of the superior HMW-GS pair(Dx5+Dy10), the contribution of the Dy10 subunit to wheat processing quality remains unclear. In this study, we elucidated the effect of Dy10 on wheat processing quality by generating and analyzing a deletion mutant(with the Dy10-null allele), and by elucidating the changes to wheat flour following the incorporation of purified Dy10. The Dy10-null allele was transcribed normally,but the Dy10 subunit was lacking. These findings implied that the Dy10-null allele reduced the glutenin:gliadin ratio and negatively affected dough strength(i.e., Zeleny sedimentation value, gluten index, and dough development and stability times) and the bread-making quality;however, it positively affected the biscuit-making quality. The incorporation of various amounts of purified Dy10 into wheat flour had a detrimental effect on biscuit-making quality. The results of this study demonstrate that the Dy10 subunit is essential for maintaining wheat dough strength. Furthermore, the Dy10-null allele may be exploited by soft wheat breeding programs.展开更多
Objective:To reconstruct pEGFP-C2-L539fs/47,a HERG nonsense mutant in eukaryotic expression plasmid,and observe the fusion protein expressed in HEK293 cells(human embryo kidney cells).Methods:After double digestion of...Objective:To reconstruct pEGFP-C2-L539fs/47,a HERG nonsense mutant in eukaryotic expression plasmid,and observe the fusion protein expressed in HEK293 cells(human embryo kidney cells).Methods:After double digestion of pcDNA3-L539fs/47 and pEGFP-C2-HERG with sbf I and Eco91 I,the small product fragment,from pcDNA3-L539fs/47,was subcloned into the big fragment of pEGFP-C2-HERG under T4 ligase.pEGFP-C2-L539fs/47 was identified by agarose gel electrophoresis and sequencing.pcDNA3-L539fs/47 and pEGFP-C2-L539fs/47 were transiently transfected into HEK293 cells by Lipofect,respectively.The expression of fusion protein in HEK293 cells was detected through immunofluorescence,laser confocal imaging scanning in vivo,Western blot and PCR.Results:Mutation region cDNA fragment(about 1 kb) and target vector fragment(about 7.2 kb) were ligated after purification and gel recovery.Agarose gel electrophoresis and sequencing successfully demonstrated eukaryotic expression plasmid pEGFP-C2-L539fs/47,constructed approximately 8.2 kb,sequencing consistent with template gene.The transfection efficiency of recombinant plasmid by fluorescence microscopy was more than60%.Western blot analysis detected pcDNA3-L539fs/47 expression of the protein size 60 KD,the expression of pEGFP-C2 fusion protein size of approximately 90 KD.The L539fs/47 gene expression in HEK293 cells was significant by PCR analysis.Confocal laser imaging showed that pEGFP-C2-L539fs/47 protein was successfully expressed in cytoplasm and cytomembrane of HEK293 cells.Conclusion:pEGFP-C2-L539fs/47 containing the HERG gene mutant was successfully constructed by double digestion method and expressed fusion protein in HEK293 cells,which laid a foundation for the further study on L539fs/47.展开更多
This study sought to elucidate the genetic correlation of cerebral venous sinus thrombosis caused by a hereditary antithrombin deficiency in a Chinese family, at the genetic and protein levels. A nonsense mutation fro...This study sought to elucidate the genetic correlation of cerebral venous sinus thrombosis caused by a hereditary antithrombin deficiency in a Chinese family, at the genetic and protein levels. A nonsense mutation from C to T on locus 6431 in exon 3B of the antithrombin gene was observed, leading to an arginine （CGA） to stop codon （TGA） change in the protein. This is the first report of this mutation in China. Ineffective heparin therapy in the propositus patient is associated with a lack of heparin binding sites after antithrombin gene mutation. Characteristic low intracranial pressure in the acute phase might be specific to this patient with cerebral venous sinus thrombosis.展开更多
Dear Editor,I am Dr.Ungsoo Samuel Kim.from Kim＇s Eye Hospital,Konyang University,Seoul,Korea.I write to present a novel mutation of GPR143 in Korean patients with X-linked congenital nystagmus by using exome sequenci...Dear Editor,I am Dr.Ungsoo Samuel Kim.from Kim＇s Eye Hospital,Konyang University,Seoul,Korea.I write to present a novel mutation of GPR143 in Korean patients with X-linked congenital nystagmus by using exome sequencing.Congenital nystagmus is an inherited ocular disorder that can occur as an X-linked condition.展开更多
·AIM:To identify potential mutations and elucidate the clinical findings of male patients and female carriers of X-Iinked retinitis pigmentosa(XLRP)in a Chinese family.·METHODS:A four generation pedigree was...·AIM:To identify potential mutations and elucidate the clinical findings of male patients and female carriers of X-Iinked retinitis pigmentosa(XLRP)in a Chinese family.·METHODS:A four generation pedigree was collected that consisted of 20 individuals.Genomic DNA was extracted from peripheral blood,and then the target fragments were amplified by PCR and sequenced directly.In addition,all affected patients and female carriers underwent comprehensively ophthalmic evaluation.·RESULTS:A novel mutation c.2865 G>A p.W955 X in RPGR gene was identified of this family,including four affected individuals and eight carriers.All male patients,aging from 7 to 31 y,tended to have more various,even potentially deleterious clinical features of RP.At the same time,individuals with heterozygous mutations(carriers)manifested a wide spectrum of clinical features.Herein,only two male patients and three female carriers manifested pathological myopia(PM).Among the female carriers,half of subjects who harbor poor visual acuity suffered esotropia or exotropia.Additionally,16.7%and 66.7%of carriers had abnormal electroretinogram(ERG)and fundus,respectively.·CONCLUSION:In this study,a novel mutation of the RPGR gene is identified,which broadens the spectrum of RPGR mutations,and elaborates the relationship between genotype and phenotype.展开更多
BACKGROUND Hereditary spherocytosis(HS)is characterized by anemia,jaundice,splenomegaly,and cholelithiasis,and is caused by abnormal genes encoding red blood cell membrane components.The most common mutations found in...BACKGROUND Hereditary spherocytosis(HS)is characterized by anemia,jaundice,splenomegaly,and cholelithiasis,and is caused by abnormal genes encoding red blood cell membrane components.The most common mutations found in HS are in the ANK1 gene.CASE SUMMARY A 4-mo-old girl was admitted to our hospital with pallor that had lasted for more than 2 mo.She presented with jaundice,anemia and splenomegaly.A heterozygous mutation of ANK1(exon23:c.G2467T:p.E823X)was identified,and the mutation was determined to be autosomal dominant.This mutation is linked to the relatively serious anemia she had after birth;this anemia improved with age.CONCLUSION The utilization of next-generation sequencing may assist with the accurate diagnosis of HS,especially in atypical cases.展开更多
Codon nonsense mutations include amber, ochre, or opal mutations according to termination codon consisting of three types (TAG, TAA and TGA). Codon nonsense mutations are also divided into natural and artificial mutat...Codon nonsense mutations include amber, ochre, or opal mutations according to termination codon consisting of three types (TAG, TAA and TGA). Codon nonsense mutations are also divided into natural and artificial mutations. We discussed the interaction of codon nonsense mutations and suppressor tRNAs in vitro and in vivo. Nonsense suppressions do not only happen in prokaryotes but also in eukaryotes. Meanwhile, the misreading of termination codon and in-corporation of nonnatural amino acids into proteins are also introduced.展开更多
This paper examines two postcolonial writings by the Nobel Prize winner Vidiadhar Surajprasad Naipaul, The Mimic Men （1969） and In a Free State （1984）. In particular, it studies how Naipaul reflects on the histori...This paper examines two postcolonial writings by the Nobel Prize winner Vidiadhar Surajprasad Naipaul, The Mimic Men （1969） and In a Free State （1984）. In particular, it studies how Naipaul reflects on the historical experiences of national nonsense--the seemingly contradictory existence of transnationality in nationality--and how he manages in his writings to keep an ethical distance from both the colonial empires and the nation-states that came up to replace the colonial empires in the postcolonial world.展开更多
＂Every saint has a past, every sinner has a future, so we＇ll keep working.＂
——“每个圣人都有过去，每个罪人都有未来。”不久前．美国微软公司创始人比尔·盖茨和“股神”沃伦·巴菲特联手呼吁美国富豪捐出至少一...＂Every saint has a past, every sinner has a future, so we＇ll keep working.＂
——“每个圣人都有过去，每个罪人都有未来。”不久前．美国微软公司创始人比尔·盖茨和“股神”沃伦·巴菲特联手呼吁美国富豪捐出至少一半个人财富用于慈善。此前．二人已分别捐出绝大多数个人财富．巴菲特捐出99％的个人财富．盖茨则承诺把大多数财富交由自己的慈善基金会处理。如今，40名资产超过10亿美元的美国富豪承诺将捐出至少一半财富，用于慈善事业．响应盖茨和巴菲特先前联手发起的号召。展开更多
＂I＇m outraged. It＇s hard for me tobelieve they would treat the family the way they have, which has been abysmally.＂——爱因斯坦1955年去世时，将其7．5万页的手稿版权和其他资产捐给了以色列耶路撒冷希伯来大学。该大学...＂I＇m outraged. It＇s hard for me tobelieve they would treat the family the way they have, which has been abysmally.＂——爱因斯坦1955年去世时，将其7．5万页的手稿版权和其他资产捐给了以色列耶路撒冷希伯来大学。该大学同时拥有他的肖像权．每年，用爱因斯坦肖像制作的视频、摇头玩偶以及万圣节面具等产品，都能产生数百万美元的效益。展开更多
＂We ask for their understanding. We are correcting deficiencies that we have noted in the implementation of our operating procedures, and none of us wanted this outcome.＂
——8月23日发生在马尼拉的劫持人质事件，警...＂We ask for their understanding. We are correcting deficiencies that we have noted in the implementation of our operating procedures, and none of us wanted this outcome.＂
——8月23日发生在马尼拉的劫持人质事件，警方与劫匪对峙十多个小时，但仍造成8名香港游客死亡。事件引起香港公众对菲律宾当局和警方的强烈愤怒。菲律宾警方承认参与营救行动的警察团队训练不够，团队领导无能．营救行动计划不周。同时．菲律宾总统阿基诺三世就自己在24日的新闻发布会上面露笑容道歉．称他当时在“表达愤怒，没有其他任何意思”，并希望得到港人的谅解。展开更多
Introduction:Urbach-Wiethe disease(or lipoid proteinosis)is an autosomal recessive genetic disease.It is caused by a mutation in the extracellular matrix protein 1 gene(ECM1),resulting in deposition of hyaline materia...Introduction:Urbach-Wiethe disease(or lipoid proteinosis)is an autosomal recessive genetic disease.It is caused by a mutation in the extracellular matrix protein 1 gene(ECM1),resulting in deposition of hyaline material at the dermoepidermal junction of the skin,around blood vessels,and at multiple other sites.Herein,we reported 3 siblings with lipoid proteinosis.Case presentation:The 3 siblings born to nonconsanguineous parents presented with hoarseness,macroglossia,yellow waxy skin,beaded papules on the eyelids,atrophic scars,and recurrent skin infections.Histopathologic examination showed hyaline deposition at the interface between the dermis and epidermis and at the basal lamina of blood vessels.Exome sequencing revealed a homozygous nonsense variant in ECM1.This variant created a premature stop codon,leading to loss of function.Both parents were heterozygous for the same mutation.Discussion:The gene responsible for lipoid proteinosis,ECM1,plays a key role in maintaining dermal homeostasis by influencing protein-protein binding and is also involved in aging and dermatoheliosis,which may explain the patients’prematurely aged appearance and dermal deposits in our cases.Lipoid proteinosis is rarely encountered in Pakistan.Around 47 variants of ECM1 have been documented,with about half involving exon 6 or 7 of the gene.The variant detected in our family was in exon 7.Genetic analysis and identification of causative variants may enhance understanding of the disease’s pathogenesis and aid better management.Conclusion:This report is a useful addition to the current knowledge base regarding this phenotypically and genetically variable genodermatosis,lipoid proteinosis,which is rarely reported in Pakistan.展开更多
Duchenne muscular dystrophy(DMD)is a fatal X-chromosome-linked genetic disease caused by dystrophin gene mutations,including nonsense mutations.1 Nonsense mutations are caused by the introduction of premature terminat...Duchenne muscular dystrophy(DMD)is a fatal X-chromosome-linked genetic disease caused by dystrophin gene mutations,including nonsense mutations.1 Nonsense mutations are caused by the introduction of premature termination codons,which prevent translation of full-length proteins.Read-through therapies show potential for addressing DMD's genetic basis;however,issues such as non-specific amino acid insertions,gene-editing delivery challenges,and clinical safety concerns have limited their progress.2,3 To address nonsense mutations,nonsense suppressor transfer RNAs(sup-tRNAs)have been proposed as a genetic therapy approach.3,4,5 In this study,we propose a new MyoAAV-delivered suppressor tRNA(sup-tRNA)strategy to restore dystrophin expression.Our approach specifically targets nonsense mutations in mdx mice and patient-derived myoblasts and cardiomyocytes,significantly increasing dystrophin levels,especially in the heart(up to 61.43%when combined with CC-90009).This combination alleviates dystrophic symptoms and improves read-through efficiency,likely by reducing translation termination factor activity.These findings highlight the potential of sup-tRNA in DMD and other nonsense mutation-related diseases.展开更多
Background The clinical use of gentamicin always lies in its antimicrobial activity in the past as an aminoglycoside antibiotic.However,in the past decade,there were considerable interests in therapeutic approaches in...Background The clinical use of gentamicin always lies in its antimicrobial activity in the past as an aminoglycoside antibiotic.However,in the past decade,there were considerable interests in therapeutic approaches in treating hereditary diseases.Some of the genodermatosis is caused by nonsense mutations that create premature termination codons and lead to the production of truncated or non-functional proteins.Gentamicin could induce readthrough of nonsense mutations and enable the synthesis of full-length proteins.We focus on previous publications on topical application of gentamicin and review its utility in genetic skin diseases.Data sources We search the MEDLINE through PubMed,EMBASE databases,and the Clinical Trials Registry Platform from January 1960 to July 2020 using the key search terms"gentamicin,topical gentamicin,genodermatosis,genetic skin diseases".Results The application of gentamicin in genodermatosis yielded promising results,both in vivo and in vitro,including Nagashima-type palmoplantar keratosis,epidermolysis bullosa,Hailey-Hailey disease,hereditary hypotrichosis simplex of the scalp,etc.Conclusions Topical gentamicin is a potential treatment option for genodermatosis caused by nonsense mutation.展开更多
Background Bardet-Biedl syndrome （BBS） is a genetically heterogeneous disease, and information about BBS in Chinese populations is very limited. The purpose of the present study was to determine the genetic cause of...Background Bardet-Biedl syndrome （BBS） is a genetically heterogeneous disease, and information about BBS in Chinese populations is very limited. The purpose of the present study was to determine the genetic cause of BBS in a Chinese Han family. Methods Clinical data were recorded for the 4-year-old female proband and the available family members. The proband was screened for mutation by Sanger sequencing for a total of 142 exons of the 12 BBS-causing genes （BBS1-BBS12）. The variants detected in the proband were further confirmed in the other family members. Results We identified a novel homozygous nonsense mutation （c.70A〉T, p.K24X） in the BBS4 gene exon 2 in the proband. Such mutant allele was predicted to cause a premature truncation in the N-terminal of the BBS4 protein, and probably induced the nonsense-mediated decay of BBS4 messenger RNAs. The proband＇s parents and brother were heterozygous for the nonsense mutant allele. It was absent in 50 Chinese control subjects. An additional rare heterozygous missense single nucleotide polymorphism （SNP） named rs200718870 in BBS10 gene was also detected in the proband, her father and her brother. Some manifestations of the proband including atypical retinitis pigmentosa, choroidal sclerosis, high myopia, and early onset of obesity might be associated with this mutation in BBS4 gene. The proband＇s father also reported surgical removal of an extra finger during childhood. Conclusions The present study described a novel nonsense mutation in BBS4 gene in a Chinese family. This homozygous mutation was predicted to completely abolish the synthesis of the BBS4 protein. We also detected a rare heterozygous missense SNP in BBSIO gene in the family, but did not find sufficient evidence to support the triallelic inheritance.展开更多
Suppressor tRNAs are engineered or naturally occurring transfer RNA molecules that have shown promise in gene therapy for diseases caused by nonsense mutations,which result in premature termination codons(PTCs)in codi...Suppressor tRNAs are engineered or naturally occurring transfer RNA molecules that have shown promise in gene therapy for diseases caused by nonsense mutations,which result in premature termination codons(PTCs)in coding sequence,leading to truncated,often nonfunctional proteins.Suppressor t RNAs can recognize and pair with these PTCs,allowing the ribosome to continue translation and produce a full-length protein.This review introduces the mechanism and development of suppressor t RNAs,compares suppressor tRNAs with other readthrough therapies,discusses their potential for clinical therapy,limitations,and obstacles.We also summarize the applications of suppressor tRNAs in both in vitro and in vivo,offering new insights into the research and treatment of nonsense mutation diseases.展开更多
Background The congenital Long QT syndrome （LQTS） is a hereditary cardiac channelopathy that is characterized by a prolonged QT interval,syncope,ventricular arrhythmias,and sudden death.The chromosome 7-linked type ...Background The congenital Long QT syndrome （LQTS） is a hereditary cardiac channelopathy that is characterized by a prolonged QT interval,syncope,ventricular arrhythmias,and sudden death.The chromosome 7-linked type 2 congenital LQTS （LQT2） is caused by gene mutations in the human ether-a-go-go-related gene （HERG）.Methods A Chinese family diagnosed with LQTS were screened for KCNQ1,HERG and SCN5A,using polymerase chain reaction （PCR）,direct sequencing,and clong sequencing.We also investigated the mRNA expression of the HERG gene.Results We identified a novel i414fs＋98X mutation in the HERG gene.The deletion mutation of 14-bp in the first transmembrane segment （S1） introduced premature termination codons （PTCs） at the end of exon 6.This mutation would result in a serious phenotype if the truncated proteins co-assembled with normal subunit to form the defective channels.But only the proband was symptomatic.Conclusions We found that the mRNA level of the HERG gene was significantly lower in 1414fs＋98X carriers than in noncarriers.We found a novel 1414fs＋98X mutation.The mRNA level supports that NMD mechanism might regulate the novel mutation.展开更多
基金Supported by Education and Teaching Reform Project of Tianjin Agricultural University(2018-B-51).
文摘Universities should take undergraduate education as the fundamental connotation of the times,and we will return to common sense,duty,original aspiration and dream,which is the basic principle of the reform and development of colleges and universities. Speeding up the construction of high-level undergraduate education and improving the ability of talent training in an all-round way,eliminating nonsensical courses and creating first-rate courses has become one of the important tasks of teaching in higher education. Starting from the standard of first-rate courses,this paper deeply analyzes the reasons for the prevalence of nonsensical courses,and expounds some ways to control nonsensical courses and create first-rate courses.
基金supported by the National Natural Science Foundation of China (31971939, 32072054, and 31901961)the Science and Technology Department of Sichuan Province, China (2019YFH0066 and 2020YFH0150)the Designing Future Wheat Strategic Program of the UK (BB/P016855/1)。
文摘High-molecular-weight glutenin subunits(HMW-GSs) are the most critical grain storage proteins that determine the unique processing qualities of wheat. Although it is a part of the superior HMW-GS pair(Dx5+Dy10), the contribution of the Dy10 subunit to wheat processing quality remains unclear. In this study, we elucidated the effect of Dy10 on wheat processing quality by generating and analyzing a deletion mutant(with the Dy10-null allele), and by elucidating the changes to wheat flour following the incorporation of purified Dy10. The Dy10-null allele was transcribed normally,but the Dy10 subunit was lacking. These findings implied that the Dy10-null allele reduced the glutenin:gliadin ratio and negatively affected dough strength(i.e., Zeleny sedimentation value, gluten index, and dough development and stability times) and the bread-making quality;however, it positively affected the biscuit-making quality. The incorporation of various amounts of purified Dy10 into wheat flour had a detrimental effect on biscuit-making quality. The results of this study demonstrate that the Dy10 subunit is essential for maintaining wheat dough strength. Furthermore, the Dy10-null allele may be exploited by soft wheat breeding programs.
基金Supported by the National Natural Science Foundation of China (No. 30800473)
文摘Objective:To reconstruct pEGFP-C2-L539fs/47,a HERG nonsense mutant in eukaryotic expression plasmid,and observe the fusion protein expressed in HEK293 cells(human embryo kidney cells).Methods:After double digestion of pcDNA3-L539fs/47 and pEGFP-C2-HERG with sbf I and Eco91 I,the small product fragment,from pcDNA3-L539fs/47,was subcloned into the big fragment of pEGFP-C2-HERG under T4 ligase.pEGFP-C2-L539fs/47 was identified by agarose gel electrophoresis and sequencing.pcDNA3-L539fs/47 and pEGFP-C2-L539fs/47 were transiently transfected into HEK293 cells by Lipofect,respectively.The expression of fusion protein in HEK293 cells was detected through immunofluorescence,laser confocal imaging scanning in vivo,Western blot and PCR.Results:Mutation region cDNA fragment(about 1 kb) and target vector fragment(about 7.2 kb) were ligated after purification and gel recovery.Agarose gel electrophoresis and sequencing successfully demonstrated eukaryotic expression plasmid pEGFP-C2-L539fs/47,constructed approximately 8.2 kb,sequencing consistent with template gene.The transfection efficiency of recombinant plasmid by fluorescence microscopy was more than60%.Western blot analysis detected pcDNA3-L539fs/47 expression of the protein size 60 KD,the expression of pEGFP-C2 fusion protein size of approximately 90 KD.The L539fs/47 gene expression in HEK293 cells was significant by PCR analysis.Confocal laser imaging showed that pEGFP-C2-L539fs/47 protein was successfully expressed in cytoplasm and cytomembrane of HEK293 cells.Conclusion:pEGFP-C2-L539fs/47 containing the HERG gene mutant was successfully constructed by double digestion method and expressed fusion protein in HEK293 cells,which laid a foundation for the further study on L539fs/47.
基金the National Natural Science Foundation of China, No. 81041019the National High-Technology Research and Development Program of China (863 Program), No.2006AA02Z436
文摘This study sought to elucidate the genetic correlation of cerebral venous sinus thrombosis caused by a hereditary antithrombin deficiency in a Chinese family, at the genetic and protein levels. A nonsense mutation from C to T on locus 6431 in exon 3B of the antithrombin gene was observed, leading to an arginine （CGA） to stop codon （TGA） change in the protein. This is the first report of this mutation in China. Ineffective heparin therapy in the propositus patient is associated with a lack of heparin binding sites after antithrombin gene mutation. Characteristic low intracranial pressure in the acute phase might be specific to this patient with cerebral venous sinus thrombosis.
文摘Dear Editor,I am Dr.Ungsoo Samuel Kim.from Kim＇s Eye Hospital,Konyang University,Seoul,Korea.I write to present a novel mutation of GPR143 in Korean patients with X-linked congenital nystagmus by using exome sequencing.Congenital nystagmus is an inherited ocular disorder that can occur as an X-linked condition.
基金Supported by Natural Science Foundation of Hebei Province(No.H2021316006)Hebei Provincial the Ministry of Health Research Fund for Medical Sciences(No.20200638)。
文摘·AIM:To identify potential mutations and elucidate the clinical findings of male patients and female carriers of X-Iinked retinitis pigmentosa(XLRP)in a Chinese family.·METHODS:A four generation pedigree was collected that consisted of 20 individuals.Genomic DNA was extracted from peripheral blood,and then the target fragments were amplified by PCR and sequenced directly.In addition,all affected patients and female carriers underwent comprehensively ophthalmic evaluation.·RESULTS:A novel mutation c.2865 G>A p.W955 X in RPGR gene was identified of this family,including four affected individuals and eight carriers.All male patients,aging from 7 to 31 y,tended to have more various,even potentially deleterious clinical features of RP.At the same time,individuals with heterozygous mutations(carriers)manifested a wide spectrum of clinical features.Herein,only two male patients and three female carriers manifested pathological myopia(PM).Among the female carriers,half of subjects who harbor poor visual acuity suffered esotropia or exotropia.Additionally,16.7%and 66.7%of carriers had abnormal electroretinogram(ERG)and fundus,respectively.·CONCLUSION:In this study,a novel mutation of the RPGR gene is identified,which broadens the spectrum of RPGR mutations,and elaborates the relationship between genotype and phenotype.
基金Supported by the Natural Science Foundation of Shanghai Science Committee,No.18ZR1431200Research Foundation of Shanghai Municipal Health Commission,No.20194Y0112Clinical Research Plan of SHDC,No.SHDC2020CR4089.
文摘BACKGROUND Hereditary spherocytosis(HS)is characterized by anemia,jaundice,splenomegaly,and cholelithiasis,and is caused by abnormal genes encoding red blood cell membrane components.The most common mutations found in HS are in the ANK1 gene.CASE SUMMARY A 4-mo-old girl was admitted to our hospital with pallor that had lasted for more than 2 mo.She presented with jaundice,anemia and splenomegaly.A heterozygous mutation of ANK1(exon23:c.G2467T:p.E823X)was identified,and the mutation was determined to be autosomal dominant.This mutation is linked to the relatively serious anemia she had after birth;this anemia improved with age.CONCLUSION The utilization of next-generation sequencing may assist with the accurate diagnosis of HS,especially in atypical cases.
文摘Codon nonsense mutations include amber, ochre, or opal mutations according to termination codon consisting of three types (TAG, TAA and TGA). Codon nonsense mutations are also divided into natural and artificial mutations. We discussed the interaction of codon nonsense mutations and suppressor tRNAs in vitro and in vivo. Nonsense suppressions do not only happen in prokaryotes but also in eukaryotes. Meanwhile, the misreading of termination codon and in-corporation of nonnatural amino acids into proteins are also introduced.
文摘This paper examines two postcolonial writings by the Nobel Prize winner Vidiadhar Surajprasad Naipaul, The Mimic Men （1969） and In a Free State （1984）. In particular, it studies how Naipaul reflects on the historical experiences of national nonsense--the seemingly contradictory existence of transnationality in nationality--and how he manages in his writings to keep an ethical distance from both the colonial empires and the nation-states that came up to replace the colonial empires in the postcolonial world.
文摘＂Every saint has a past, every sinner has a future, so we＇ll keep working.＂
——“每个圣人都有过去，每个罪人都有未来。”不久前．美国微软公司创始人比尔·盖茨和“股神”沃伦·巴菲特联手呼吁美国富豪捐出至少一半个人财富用于慈善。此前．二人已分别捐出绝大多数个人财富．巴菲特捐出99％的个人财富．盖茨则承诺把大多数财富交由自己的慈善基金会处理。如今，40名资产超过10亿美元的美国富豪承诺将捐出至少一半财富，用于慈善事业．响应盖茨和巴菲特先前联手发起的号召。
文摘＂I＇m outraged. It＇s hard for me tobelieve they would treat the family the way they have, which has been abysmally.＂——爱因斯坦1955年去世时，将其7．5万页的手稿版权和其他资产捐给了以色列耶路撒冷希伯来大学。该大学同时拥有他的肖像权．每年，用爱因斯坦肖像制作的视频、摇头玩偶以及万圣节面具等产品，都能产生数百万美元的效益。
文摘＂We ask for their understanding. We are correcting deficiencies that we have noted in the implementation of our operating procedures, and none of us wanted this outcome.＂
——8月23日发生在马尼拉的劫持人质事件，警方与劫匪对峙十多个小时，但仍造成8名香港游客死亡。事件引起香港公众对菲律宾当局和警方的强烈愤怒。菲律宾警方承认参与营救行动的警察团队训练不够，团队领导无能．营救行动计划不周。同时．菲律宾总统阿基诺三世就自己在24日的新闻发布会上面露笑容道歉．称他当时在“表达愤怒，没有其他任何意思”，并希望得到港人的谅解。
文摘Introduction:Urbach-Wiethe disease(or lipoid proteinosis)is an autosomal recessive genetic disease.It is caused by a mutation in the extracellular matrix protein 1 gene(ECM1),resulting in deposition of hyaline material at the dermoepidermal junction of the skin,around blood vessels,and at multiple other sites.Herein,we reported 3 siblings with lipoid proteinosis.Case presentation:The 3 siblings born to nonconsanguineous parents presented with hoarseness,macroglossia,yellow waxy skin,beaded papules on the eyelids,atrophic scars,and recurrent skin infections.Histopathologic examination showed hyaline deposition at the interface between the dermis and epidermis and at the basal lamina of blood vessels.Exome sequencing revealed a homozygous nonsense variant in ECM1.This variant created a premature stop codon,leading to loss of function.Both parents were heterozygous for the same mutation.Discussion:The gene responsible for lipoid proteinosis,ECM1,plays a key role in maintaining dermal homeostasis by influencing protein-protein binding and is also involved in aging and dermatoheliosis,which may explain the patients’prematurely aged appearance and dermal deposits in our cases.Lipoid proteinosis is rarely encountered in Pakistan.Around 47 variants of ECM1 have been documented,with about half involving exon 6 or 7 of the gene.The variant detected in our family was in exon 7.Genetic analysis and identification of causative variants may enhance understanding of the disease’s pathogenesis and aid better management.Conclusion:This report is a useful addition to the current knowledge base regarding this phenotypically and genetically variable genodermatosis,lipoid proteinosis,which is rarely reported in Pakistan.
基金supported by the National Key Research and Development Program of China(No.2022YFC2703600)the National Natural Science Foundation of China(No.81930121).
文摘Duchenne muscular dystrophy(DMD)is a fatal X-chromosome-linked genetic disease caused by dystrophin gene mutations,including nonsense mutations.1 Nonsense mutations are caused by the introduction of premature termination codons,which prevent translation of full-length proteins.Read-through therapies show potential for addressing DMD's genetic basis;however,issues such as non-specific amino acid insertions,gene-editing delivery challenges,and clinical safety concerns have limited their progress.2,3 To address nonsense mutations,nonsense suppressor transfer RNAs(sup-tRNAs)have been proposed as a genetic therapy approach.3,4,5 In this study,we propose a new MyoAAV-delivered suppressor tRNA(sup-tRNA)strategy to restore dystrophin expression.Our approach specifically targets nonsense mutations in mdx mice and patient-derived myoblasts and cardiomyocytes,significantly increasing dystrophin levels,especially in the heart(up to 61.43%when combined with CC-90009).This combination alleviates dystrophic symptoms and improves read-through efficiency,likely by reducing translation termination factor activity.These findings highlight the potential of sup-tRNA in DMD and other nonsense mutation-related diseases.
基金supported by Children's Medicine Research Project of Beijing Children's Hospital,Capital Medical University(YZZD202002).
文摘Background The clinical use of gentamicin always lies in its antimicrobial activity in the past as an aminoglycoside antibiotic.However,in the past decade,there were considerable interests in therapeutic approaches in treating hereditary diseases.Some of the genodermatosis is caused by nonsense mutations that create premature termination codons and lead to the production of truncated or non-functional proteins.Gentamicin could induce readthrough of nonsense mutations and enable the synthesis of full-length proteins.We focus on previous publications on topical application of gentamicin and review its utility in genetic skin diseases.Data sources We search the MEDLINE through PubMed,EMBASE databases,and the Clinical Trials Registry Platform from January 1960 to July 2020 using the key search terms"gentamicin,topical gentamicin,genodermatosis,genetic skin diseases".Results The application of gentamicin in genodermatosis yielded promising results,both in vivo and in vitro,including Nagashima-type palmoplantar keratosis,epidermolysis bullosa,Hailey-Hailey disease,hereditary hypotrichosis simplex of the scalp,etc.Conclusions Topical gentamicin is a potential treatment option for genodermatosis caused by nonsense mutation.
文摘Background Bardet-Biedl syndrome （BBS） is a genetically heterogeneous disease, and information about BBS in Chinese populations is very limited. The purpose of the present study was to determine the genetic cause of BBS in a Chinese Han family. Methods Clinical data were recorded for the 4-year-old female proband and the available family members. The proband was screened for mutation by Sanger sequencing for a total of 142 exons of the 12 BBS-causing genes （BBS1-BBS12）. The variants detected in the proband were further confirmed in the other family members. Results We identified a novel homozygous nonsense mutation （c.70A〉T, p.K24X） in the BBS4 gene exon 2 in the proband. Such mutant allele was predicted to cause a premature truncation in the N-terminal of the BBS4 protein, and probably induced the nonsense-mediated decay of BBS4 messenger RNAs. The proband＇s parents and brother were heterozygous for the nonsense mutant allele. It was absent in 50 Chinese control subjects. An additional rare heterozygous missense single nucleotide polymorphism （SNP） named rs200718870 in BBS10 gene was also detected in the proband, her father and her brother. Some manifestations of the proband including atypical retinitis pigmentosa, choroidal sclerosis, high myopia, and early onset of obesity might be associated with this mutation in BBS4 gene. The proband＇s father also reported surgical removal of an extra finger during childhood. Conclusions The present study described a novel nonsense mutation in BBS4 gene in a Chinese family. This homozygous mutation was predicted to completely abolish the synthesis of the BBS4 protein. We also detected a rare heterozygous missense SNP in BBSIO gene in the family, but did not find sufficient evidence to support the triallelic inheritance.
基金supported by the National Natural Science Foundation of China(82371861)Key R&D Program of Zhejiang(2024SSYS0020)+1 种基金Henan Province Key Research and Promotion Project(242102311023)the Starting Fund from Zhejiang University。
文摘Suppressor tRNAs are engineered or naturally occurring transfer RNA molecules that have shown promise in gene therapy for diseases caused by nonsense mutations,which result in premature termination codons(PTCs)in coding sequence,leading to truncated,often nonfunctional proteins.Suppressor t RNAs can recognize and pair with these PTCs,allowing the ribosome to continue translation and produce a full-length protein.This review introduces the mechanism and development of suppressor t RNAs,compares suppressor tRNAs with other readthrough therapies,discusses their potential for clinical therapy,limitations,and obstacles.We also summarize the applications of suppressor tRNAs in both in vitro and in vivo,offering new insights into the research and treatment of nonsense mutation diseases.
文摘Background The congenital Long QT syndrome （LQTS） is a hereditary cardiac channelopathy that is characterized by a prolonged QT interval,syncope,ventricular arrhythmias,and sudden death.The chromosome 7-linked type 2 congenital LQTS （LQT2） is caused by gene mutations in the human ether-a-go-go-related gene （HERG）.Methods A Chinese family diagnosed with LQTS were screened for KCNQ1,HERG and SCN5A,using polymerase chain reaction （PCR）,direct sequencing,and clong sequencing.We also investigated the mRNA expression of the HERG gene.Results We identified a novel i414fs＋98X mutation in the HERG gene.The deletion mutation of 14-bp in the first transmembrane segment （S1） introduced premature termination codons （PTCs） at the end of exon 6.This mutation would result in a serious phenotype if the truncated proteins co-assembled with normal subunit to form the defective channels.But only the proband was symptomatic.Conclusions We found that the mRNA level of the HERG gene was significantly lower in 1414fs＋98X carriers than in noncarriers.We found a novel 1414fs＋98X mutation.The mRNA level supports that NMD mechanism might regulate the novel mutation.
