A novel nonsense mutation of GPR143 gene in a Korean kindred with X-linked congenital nystagmus

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.

Targeted next-generation sequencing identifies a novel nonsense mutation in ANK1 for hereditary spherocytosis:A case report

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.

Interaction of nonsense suppressor tRNAs and codon nonsense mutations or termination codons

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.

Sense and Nonsense

“Send cash，not ash!” ——经济崩溃．火山喷发．冰岛大乱欧洲！2008年金融危机期间冰岛主要银行倒闭．致使英国与荷兰三十余万人积蓄血本无归，冰岛公投拒赔他国储户损失。2010年44以来冰岛南部火山持续喷发，火山灰严重影响欧洲航运与旅游业．欧盟委员会估计其造成的损失高达15亿至25亿欧元。

Sense and Nonsense

＂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。

Sense and Nonsense

＂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。

Sense and Nonsense

“只有蒸汽，没有引擎。” ——《纽约时报》专栏作家Thomas L．Friedman如此评价美国沸沸扬扬的“茶党”运动（Tea Party movement）。

Sense and Nonsense

＂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。

Application of topical gentamicin ointment in the treatment of Nagashima-type palmoplantar keratosis in children with a nonsense mutation

Importance:Nagashima-type palmoplantar keratosis(NPPK)is a hereditary dermatosis mostly caused by a nonsense mutation in SERPINB7.Despite the increasing interest in readthrough gentamicin treatment of NPPK,clinical evidence for this treatment is limited.Objective:This study aimed to provide further evidence for the use of topical gentamicin in the treatment of NPPK in children with nonsense mutations.Methods:We designed a bilaterally controlled study of topical gentamicin ointment.Children diagnosed with NPPK carrying nonsense mutations were enrolled in this study.A 0.1%gentamicin ointment was applied to one hand and an emollient to the other for 3 months.A bilateral comparison of the visual analog scale scores for clinical manifestations and safety was performed.Results:Ten children with NPPK were included in this study.In comparison with the emollient side,the topical gentamicin side showed significant improvements in hyperkeratosis,erythema,maceration,and desquamation after 1 and 3 months of treatment(P<0.05).However,hyperhidrosis and odor did not improve significantly.No adverse events were observed during the systemic safety monitoring examinations.Interpretation:Topical gentamicin ointment showed good safety in the treatment of NPPK with nonsense mutations,indicating that it is a promising therapeutic choice in children with NPPK.

A novel nonsense mutation in BBS4 gene identified in a Chinese family with Bardet-Biedl syndrome

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.

Truth and Nonsense:A Unified Reading of the Tractatus

Upon reading the Tractatus Logico-Philosophicus,readers might be confused about the nature of the book,since there seems to be a paradox introduced by the author’s two claims:a)the book conveys truths;b)propositions in the book are nonsense.Commentators disagree as to how best to resolve this paradox.Some hold that there are ineffable truths conveyed by nonsense propositions.Others deny this kind of truth,arguing that the book is not all nonsense,for there are some propositions in the book expressing at least the therapeutic truth that philosophical propositions are just nonsense.Recently,some interpreters have claimed that there is no truth at all.While the incoherence of the context is genuine,the purpose of the book is ethical.By diagnosing these interpretations,this paper intends to provide a new perspective toward reading the book by resolving the paradox.The truth of the Tractatus is not a propositional truth,but a specific true thought.The nonsense of the Tractatus is a transcending nonsense,rather than a pure nonsense.The book intends to attain the true thought about the mystical ethics by way of transcending nonsense.In this case,the Tractatus is not an incoherent work at all,since the paradox is not genuine.The fact that the nonsense part is a means to fulfill its ethical purpose makes the book a unified whole.

Molecular mechanism of microRNA125 regulating human coagulation factor IX gene with nonsense mutation

Objective To construct human coagulation factorⅨmini-gene(Mini-h F9)and some nonsense mutants,detect the levels of the Mini-h F9 mRNA,and analyze the molecular mechanism of microRNA125 regulating F9gene with nonsense mutation.Methods Three nonsense mutants were obtained by using PCR mutagenesis to ana-

Effect of high-molecular-weight glutenin subunit Dy10 on wheat dough properties and end-use quality

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.

Antithrombin gene Arg197Stop mutation-associated venous sinus thrombosis in a Chinese family

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.

A novel mutation of RPGR in a Chinese family with X-linked retinitis pigmentosa

·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.

A Preliminary Study on Eliminating Nonsensical Courses and Creating First-rate Courses: Taking the Basic Mathematics Course in University as an Example

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.

Application of topical gentamicin-a new era in the treatment of genodermatosis

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.

A novel deletion-frameshift mutation in the S1 region of HERG gene in a Chinese family with long QT syndrome

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.

RNA-based therapies in animal models of Leber congenital amaurosis causing blindness

Leber congenital amaurosis(LCA)is a severe,genetically heterogeneous recessive eye disease in which∼35%of genemutations are in-frame nonsensemutations coding for loss-of-function premature termination codons(PTCs)inmRNA.Nonsense suppression therapy allows read-through of PTCs leading to production of full-length protein.A limitation of nonsense suppression is that nonsense-mediated decay(NMD)degrades PTC-containing RNA transcripts.The purpose of this study was to determine whether inhibition of NMD could improve nonsense suppression efficacy in vivo.Using a high-throughput approach in the recessive cep290 zebrafish model of LCA(cep290;Q1223X),we first tested the NMD inhibitor Amlexanox in combination with the nonsense suppression drug Ataluren.We observed reduced retinal cell death and improved visual function.With these positive data,we next investigated whether this strategy was also applicable across species in two mammalianmodels:Rd12(rpe65;R44X)and Rd3(rd3;R107X)mouse models of LCA.In the Rd12 model,cell death was reduced,RPE65 protein was produced,and in vivo visual function testing was improved.We establish for the first time that the mechanism of action of Amlexanox in Rd12 retina was through reduced UPF1 phosphorylation.In the Rd3 model,however,no beneficial effect was observed with Ataluren alone or in combination with Amlexanox.This variation in response establishes that some forms of nonsensemutation LCA can be targeted by RNA therapies,but that this needs to be verified for each genotype.The implementation of precision medicine by identifying better responders to specific drugs is essential for development of validated retinal therapies.