We analyzed the clinical features and NF1 gene mutation in a Chinese pedigree of neurofibromatosis type 1（NF1）. Three members of this family were NF1 patients presenting with different clinical phenotypes and the ot...We analyzed the clinical features and NF1 gene mutation in a Chinese pedigree of neurofibromatosis type 1（NF1）. Three members of this family were NF1 patients presenting with different clinical phenotypes and the others were asymptomatic. Exons of NF1 were amplified by polymerase chain reaction, sequenced, compared with a reference database. One novel NF1 frame-shift mutation c.703_704delTA, which resulted in a premature stop signal at codon 720 and the synthesis of truncated, was revealed. This mutation segregated with the NF1 members is likely responsible for the pathogenesis of NF1 in the family.展开更多
Inbreeding increases genome homozygosity within populations,which can exacerbate inbreeding depression by exposing homozygous deleterious alleles that are responsible for declines in fitness traits.In small population...Inbreeding increases genome homozygosity within populations,which can exacerbate inbreeding depression by exposing homozygous deleterious alleles that are responsible for declines in fitness traits.In small populations,genetic purging that occurs under the pressure of natural selection acts as an opposing force,contributing to a reduction of deleterious alleles.Both inbreeding and genetic purging are paramount in the field of conservation genomics.The Amur tiger(Panthera tigris altaica)lives in small populations in the forests of Northeast Asia and is among the most endangered animals on the planet.Using genome-wide assessment and comparison,we reveal substantially higher and more extensive inbreeding in wild Amur tigers(F_(ROH)=0.50)than in captive individuals(F_(ROH)=0.24).However,a relatively reduced number of lossof-function mutations in wild Amur tigers is observed compared to captive individuals,indicating genetic purging of inbreeding load with relatively large-effect alleles.The higher ratio of homozygous mutation load and number of fixed damaging alleles in the wild population indicates a less-efficient genetic purging,with purifying selection also contributing to this process.These findings provide valuable insights for the future conservation of Amur tigers.展开更多
BACKGROUND Thrombophilia contributes to a significant increased risk of venous thromboembolism and can be either inherited or acquired.Hereditary thrombophilia may arise from various gene mutations,some of which have ...BACKGROUND Thrombophilia contributes to a significant increased risk of venous thromboembolism and can be either inherited or acquired.Hereditary thrombophilia may arise from various gene mutations,some of which have not even been adequately reported or poorly understood.Previous studies reported a rare and novel missense mutation in the prothrombin gene(p.Arg596Gln),known as prothrombin Belgrade.The mechanisms and therapeutic strategies associated with prothrombin Belgrade mutation have not been fully elucidated.CASE SUMMARY We present the case of a 26-year-old woman with recurrent systemic thrombosis induced by prothrombin Belgrade mutation.The patient suffered from cerebral venous sinus thrombosis that rapidly progressed to systemic thrombosis,alongside a family history of cerebral thrombosis,and no traditional risk factors or abnormal coagulation function.Whole-genome sequencing detected a novel and rare heterozygous prothrombin missense mutation,c.1787G>T(p.Arg596Gln),which was responsible for the major etiology of the systemic thrombosis.CONCLUSION This case strengthens our understanding about hereditary basis of thrombophilia and provokes considerations for therapeutic options on prothrombin Belgrade mutation.展开更多
BACKGROUND Through deeper understanding of targetable driver mutations in non-small-cell lung cancer(NSCLC)over the past years,some patients with driver mutations have benefited from the targeted molecular therapies.A...BACKGROUND Through deeper understanding of targetable driver mutations in non-small-cell lung cancer(NSCLC)over the past years,some patients with driver mutations have benefited from the targeted molecular therapies.Although the anaplastic lymphoma kinase and BRAF mutations are not frequent subtypes in NSCLC,the availability of several targeted-drugs has been confirmed through a series of clinical trials.But little is clear about the proper strategy in rare BRAF G469A mutation,not to mention co-exhibition of anaplastic lymphoma kinase and BRAF G469A mutations,which is extremely rare in NSCLC.CASE SUMMARY We present a patient to stage IVA lung adenocarcinoma with coexisting echinoderm microtubule associated protein like-4 rearrangement and BRAF G469A mutation.She received several targeted drugs with unintended resistance and suffered from unbearable adverse events.CONCLUSION Due to the rarity of co-mutations,the case not only enriches the limited literature on NSCLC harbouring BRAF G469A and echinoderm microtubule associated protein like-4 mutations,but also suggests the efficacy and safety of specific multiple-drug therapy in such patients.展开更多
Objective:Keratoconus(KC)is a progressive corneal ectasia disorder,arising from a myriad of causes including genetic predispositions,environmental factors,biomechanical influences,and inflammatory reactions.This study...Objective:Keratoconus(KC)is a progressive corneal ectasia disorder,arising from a myriad of causes including genetic predispositions,environmental factors,biomechanical influences,and inflammatory reactions.This study aims to identify potential pathogenetic gene mutations in patients with sporadic KC in the Han Chinese population.Methods:Twenty-five patients with primary KC as well as 50 unrelated population matched healthy controls,were included in this study to identify potential pathogenic gene mutations among sporadic KC patients in the Han Chinese population.Sanger sequencing and whole-exome sequencing(WES)were used to analyze mutations in the zinc finger protein 469(ZNF469)gene.Bioinformatics analysis was conducted to explore the potential role of ZNF469 in KC pathogenesis.Results:Five novel heterozygous missense variants were identified in KC patients.Among them,2 compound heterozygous variants,c.8986G>C(p.E2996Q)with c.11765A>C(p.D3922A),and c.4423C>G(p.L1475V)with c.10633G>A(p.G3545R),were determined to be possible pathogenic factors for KC.Conclusion:Mutations in the ZNF469 gene may contribute to the development of KC in the Han Chinese population.These mutation sites may provide valuable information for future genetic screening of KC patients and their families.展开更多
Sotos syndrome is characterized by overgrowth features and is caused by alterations in the nuclear receptor binding SET domain protein 1 gene.Attentiondeficit/hyperactivity disorder(ADHD)is considered a neurodevelopme...Sotos syndrome is characterized by overgrowth features and is caused by alterations in the nuclear receptor binding SET domain protein 1 gene.Attentiondeficit/hyperactivity disorder(ADHD)is considered a neurodevelopment and psychiatric disorder in childhood.Genetic characteristics and clinical presentation could play an important role in the diagnosis of Sotos syndrome and ADHD.Magnetic resonance imaging(MRI)has been used to assess medical images in Sotos syndrome and ADHD.The images process is considered to display in MRI while wavelet fusion has been used to integrate distinct images for achieving more complete information in single image in this editorial.In the future,genetic mechanisms and artificial intelligence related to medical images could be used in the clinical diagnosis of Sotos syndrome and ADHD.展开更多
Objective:To investigate the clinical and molecular genetic characteristics of Chinese adolescents with maturity-onset diabetes of the young type 2(MODY 2)and the safety and efficacy of recombinant human growth hormon...Objective:To investigate the clinical and molecular genetic characteristics of Chinese adolescents with maturity-onset diabetes of the young type 2(MODY 2)and the safety and efficacy of recombinant human growth hormone(r-hGH).Methods:The clinical features and laboratory data of a family with MODY 2 combined with partial growth hormone deficiency(pGHD),diagnosed at the Fourth Clinical Medical College of Xinjiang Medical University,were analyzed.DNA was extracted from peripheral blood using the column method,and Sanger sequencing was conducted to analyze the glucokinase(GCK),hepatocyte nuclear factor 1α(HNF1α),and hepatocyte nuclear factor 4α(HNF4α)in the proband and relevant family members.Results:A heterozygous mutation in GCK(Reference sequence:NM_000162,location:Exon 10)c.1340G>A(p.R447Q)was detected in three family members(the proband,the proband’s younger brother,and their mother).The proband also had pGHD.Conclusion:GCK mutations causing MODY 2 exist in the Chinese population,and the combined treatment with r-hGH is safe and effective.展开更多
Certain amino acids changes in the human Na^(+)/K^(+)-ATPase pump,ATPase Na^(+)/K^(+)transporting subunit alpha 1(ATP1A1),cause Charcot-Marie-Tooth disease type 2(CMT2)disease and refractory seizures.To develop in viv...Certain amino acids changes in the human Na^(+)/K^(+)-ATPase pump,ATPase Na^(+)/K^(+)transporting subunit alpha 1(ATP1A1),cause Charcot-Marie-Tooth disease type 2(CMT2)disease and refractory seizures.To develop in vivo models to study the role of Na^(+)/K^(+)-ATPase in these diseases,we modified the Drosophila gene homolog,Atpα,to mimic the human ATP1A1 gene mutations that cause CMT2.Mutations located within the helical linker region of human ATP1A1(I592T,A597T,P600T,and D601F)were simultaneously introduced into endogenous Drosophila Atpαby CRISPR/Cas9-mediated genome editing,generating the Atpα^(TTTF)model.In addition,the same strategy was used to generate the corresponding single point mutations in flies(Atpα^(I571T),Atpα^(A576T),Atpα^(P579T),and Atpα^(D580F)).Moreover,a deletion mutation(Atpα^(mut))that causes premature termination of translation was generated as a positive control.Of these alleles,we found two that could be maintained as homozygotes(Atpα^(I571T)and Atpα^(P579T)).Three alleles(Atpα^(A576T),Atpα^(P579)and Atpα^(D580F))can form heterozygotes with the Atpαmut allele.We found that the Atpαallele carrying these CMT2-associated mutations showed differential phenotypes in Drosophila.Flies heterozygous for Atpα^(TTTF)mutations have motor performance defects,a reduced lifespan,seizures,and an abnormal neuronal morphology.These Drosophila models will provide a new platform for studying the function and regulation of the sodium-potassium pump.展开更多
Single-stranded DNA-binding proteins(SSBs)play essential roles in the replication,recombination and repair processes of organellar DNA molecules.In Arabidopsis thaliana,SSBs are encoded by a small family of two genes(...Single-stranded DNA-binding proteins(SSBs)play essential roles in the replication,recombination and repair processes of organellar DNA molecules.In Arabidopsis thaliana,SSBs are encoded by a small family of two genes(SSB1 and SSB2).However,the functional divergence of these two SSB copies in plants remains largely unknown,and detailed studies regarding their roles in the replication and recombination of organellar genomes are still incomplete.In this study,phylogenetic,gene structure and protein motif analyses all suggested that SSB1 and SSB2 probably diverged during the early evolution of seed plants.Based on accurate long-read sequencing results,ssb1 and ssb2 mutants had decreased copy numbers for both mitochondrial DNA(mtDNA)and plastid DNA(ptDNA),accompanied by a slight increase in structural rearrangements mediated by intermediate-sized repeats in mt genome and small-scale variants in both genomes.Our findings provide an important foundation for further investigating the effects of DNA dosage in the regulation of mutation frequencies in plant organellar genomes.展开更多
In renewing tissues,mutations conferring selective advantage may result in clonal expansions1-4.In contrast to somatic tissues,mutations driving clonal expansions in spermatogonia(CES)are also transmitted to the next ...In renewing tissues,mutations conferring selective advantage may result in clonal expansions1-4.In contrast to somatic tissues,mutations driving clonal expansions in spermatogonia(CES)are also transmitted to the next generation.This results in an effective increase of de novo mutation rate for CES drivers5-8.CES was originally discovered through extreme recurrence of de novo mutations causing Apert syndrome5.Here,we develop a systematic approach to discover CES drivers as hotspots of human de novo mutation.Our analysis of 54,715 trios ascertained for rare conditions9-13,6,065 control trios12,14-19 and population variation from 807,162 mostly healthy individuals20 identifies genes manifesting rates of de novo mutations inconsistent with plausible models of disease ascertainment.We propose 23 genes hypermutable at loss-of-function(LoF)sites as candidate CES drivers.An extra 17 genes feature hypermutable missense mutations at individual positions,suggesting CES acting through gain of function.CES increases the average mutation rate roughly 17-fold for LoF genes in both control trios and sperm and roughly 500-fold for pooled gain-of-function sites in sperm21.Positive selection in the male germline elevates the prevalence of genetic disorders and increases polymorphism levels,masking the effect of negative selection in human populations.展开更多
Imagine a future where a single vaccine could protect you from a multitude of influenza strains,offering broad immunity with minimal risk.This vision is now closer to reality,thanks to a recent study that harnesses th...Imagine a future where a single vaccine could protect you from a multitude of influenza strains,offering broad immunity with minimal risk.This vision is now closer to reality,thanks to a recent study that harnesses the power of cellular proteins to create a new generation of live attenuated vaccines that outsmart flu’s relentless mutations.展开更多
As the study of vascular anomalies progresses,it is imperative for plastic surgeons to individualize their in-depth research and practice to develop more effective and personalized treatment plans.Recent advancements ...As the study of vascular anomalies progresses,it is imperative for plastic surgeons to individualize their in-depth research and practice to develop more effective and personalized treatment plans.Recent advancements in genome sequencing technology have highlighted the importance of vascular endothelial growth factor(VEGF)and its receptor(VEGFR)in the formation and alteration of vascularity.However,definitive reports regarding mutations associated with this locus and treatment experiences remain scarce.Herein,we report a clinical case of multiple venous malformations with mutations in VEGFR3(FLT4).We implemented a comprehensive approach,including local lesion excision of the left foot and trunk,oral propranolol administration,and local physiotherapy.After two years of follow-up,the patient’s left foot venous malformation did not recur,and he expressed satisfaction with the outcomes of the combined therapy.This case offers valuable insights into the clinical management of this mutant type and similar presentations of multiple venous malformations.展开更多
Objective:To investigate mutations in the Chikungunya(CHIKV)envelope genome region and evaluate their potential impact on B lymphocyte epitopes via in silico analysis.Methods:E1,E2 and 6K protein genes were sequenced ...Objective:To investigate mutations in the Chikungunya(CHIKV)envelope genome region and evaluate their potential impact on B lymphocyte epitopes via in silico analysis.Methods:E1,E2 and 6K protein genes were sequenced from viral RNA isolated from 13 CHIKV-positive serum samples from Alagoas State,Brazil,during the 2016 outbreak.Phylogenetic analysis,experimental epitope identification in the immune epitope database(IEDB)and in silico approaches were employed to predict the potential impact of the detected mutations.Results:The sequences were clustered via phylogenetic analysis.The CHIKV isolates belong to the ECSA genotype,with 13 detected amino acid mutations.Five mutations are located on the surface of the viral particle in regions critical for cellular receptor interaction.Nine mutations are known experimentally validated epitopes for B and T cells.In B-cell epitope predictions,mutations affect sequences within three conformational epitopes in E2 and one in E1,as well as linear epitopes.Notably,the E2-G60D mutation found in the Alagoas strain has been previously reported to influence the vector competence of Aedes aegypti,the primary vector in Brazil.Conclusions:Genomic surveillance and an in-depth understanding of viral mutations are crucial for adapting public health strategies and improving the outbreak response.These findings could have significant public health implications,such as the development of more effective vaccines,diagnostic tests,and antiviral therapies.展开更多
The use of RNA interference(RNAi)technology to control pests is explored by researchers globally.Even though RNA is a new class of pest control compound unlike conventional chemical pesticides,the evolution of pest re...The use of RNA interference(RNAi)technology to control pests is explored by researchers globally.Even though RNA is a new class of pest control compound unlike conventional chemical pesticides,the evolution of pest resistance needs to be considered.Here,we first investigate RNAi-based biopesticide resistance of Fusarium asiaticum,which is responsible for devastating diseases of plants,for example,Fusarium head blight.Five resistant strains were isolated from 500 strains that treated with UV-mutagenesis.The mutation common to all of the five resistant mutants occurred in the gene encoding Dicer2(point mutations at codon 1005 and 1007),which were under strong purifying selection pressure.To confirm whether the mutations in Dicer2 confer resistance to RNAi,we exchanged the Dicer2 locus between the sensitive strain and the resistant strain by homologous double exchange.The transformed mutants,Dicer2^(R1005D)and Dicer2^(E1007H),exhibited resistance to dsRNA in vitro.Further study showed that mutations of R1005D and E1007H affected the intramolecular interactions of Dicer2,resulting in the dysfunction of RNase III domain of Dicer2.The amount of sRNAs produced by Dicer2^(R1005D)and Dicer2^(E1007H)was extremely reduced along with variation of sRNA length.Together,these findings revealed a new potential mechanism of RNAi resistance and provided insight into RNAi-related biopesticide deployment for fungal control.展开更多
Dear Editor,Mutations in genomic sequences exhibit a strong correlation with various pathological processes of cancers[1].Currently,the next-generation sequencing technique[2]and polymerase chain reaction(PCR)were the...Dear Editor,Mutations in genomic sequences exhibit a strong correlation with various pathological processes of cancers[1].Currently,the next-generation sequencing technique[2]and polymerase chain reaction(PCR)were the established benchmarks for analyzing DNA mutations.However,the two methods necessitate intricate experimental preparation,costly instrumentation,and skilled personnel,making them challenging for rapid mutations analysis.More importantly,these methods lack adequate accuracy for one base mutations analysis[3].Therefore,the development of a reliable and exceptionally sensitive mutation analysis approach holds immense importance in cancer diagnosis and treatment.展开更多
The honey badger algorithm(HBA),as a new swarm intelligence(SI)optimization algorithm,has shown certain effectiveness in its applications.Aiming at the problems of unsatisfactory initial population distribution of HBA...The honey badger algorithm(HBA),as a new swarm intelligence(SI)optimization algorithm,has shown certain effectiveness in its applications.Aiming at the problems of unsatisfactory initial population distribution of HBA,poor ability to avoid local optimum,and slow convergence speed,this paper proposes a multi-strategy improved HBA based on periodical mutation and t-distribution perturbation,called MHBA.Firstly,a good point set population initialization is introduced to get a uniform initial population.Secondly,periodic mutation and t-distribution perturbation are successively used to improve the algorithm’s ability to avoid local optimum.Finally,the density factor is improved for balancing exploration and exploitation.By comparing MHBA with HBA and 7 other SIs on 6 benchmark functions,it is evident that the performance of MHBA is far superior to HBA.In addition,by applying MHBA to robot path planning,MHBA can identify the shortest path more quickly and consistently compared with competitors.展开更多
Chronic pancreatitis(CP)is a progressive and irreversible fibroinflammatory disease that markedly increases susceptibility to pancreatic cancer and remains without effective targeted therapies.Among the genetic contri...Chronic pancreatitis(CP)is a progressive and irreversible fibroinflammatory disease that markedly increases susceptibility to pancreatic cancer and remains without effective targeted therapies.Among the genetic contributors to CP,the carboxypeptidase A1 p.Ser282Pro(CPA1^(S282P))variant has been proposed to promote disease through misfolding-induced endoplasmic reticulum stress(ERS),although the broader pathogenic landscape remains incompletely defined.This study generated a rabbit model mimicking the human CPA1S282P mutation using the SpRY-ABE-8.17 system.Homozygous CPA1^(S282P)rabbits exhibited characteristic human CP phenotypes following alcohol induction,including visceral pain,elevated serum lipase and amylase,inflammatory cell infiltration,and extensive pancreatic fibrosis.Biochemical analyses confirmed that the p.S282P mutation induced CPA1 misfolding and elevated the expression of ERS markers GRP78 and CHOP in both transfected HEK293T cells and homozygous mutant rabbits.Notably,the CPA1^(S282P)mutation markedly disrupted intra-pancreatic lipid homeostasis,contributing to the development of CP in mutant rabbits.This study successfully established the first rabbit model of CP that accurately recapitulates CP caused by a defined human point mutation.Additionally,this study provides insights into a previously unrecognized link between CPA1 and intra-pancreatic lipid metabolism,offering a foundation for identifying novel therapeutic targets for human CP.展开更多
BACKGROUND Pancreatic cancer(PC)is a highly malignant tumor that is resistant to chemotherapy,radiotherapy and immunotherapy.Combination chemotherapy regimens are the standard first-line regimens for metastatic diseas...BACKGROUND Pancreatic cancer(PC)is a highly malignant tumor that is resistant to chemotherapy,radiotherapy and immunotherapy.Combination chemotherapy regimens are the standard first-line regimens for metastatic disease,with a median survival<12 months.Although recurrent genomic alterations such as the BRAF V600E mutation have been reported in PC,evidence supporting the clinical effectiveness of molecularly guided targeted therapies is limited.CASE SUMMARY We report a case of a 33-year-old male who was referred to our department with weight loss of 5 kg in 2 months,anorexia and abdominal pain.Imaging showed extensive lesions involving the pancreas,liver,bones,muscles and lymph nodes accompanied by elevated carbohydrate antigen 19-9(CA19-9)and carcinoembryonic antigen(CEA).Biopsy yielded a diagnosis of PC.Treatment with gemcitabine and nab-paclitaxel was initiated,but the disease progressed in<2 months even though the patient’s general condition improved.Molecular testing revealed the presence of BRAF mutation.Dabrafenib/trametinib combination therapy was introduced,and the patient was treated for 2 months with a decrease in CA19-9 and CEA levels,but he died after 2 months of treatment.CONCLUSION BRAF alterations are infrequent in PC.This case highlights the significance of molecular profiling in patients with PC,especially in patients with a high tumor burden.展开更多
The CRISPR/Cas9 system has shown great promise in engineering targeted mutations in a genome.The efficiency of Cas9-mediated genome editing is temperature sensitive.A high-temperature regime can increase the mutation ...The CRISPR/Cas9 system has shown great promise in engineering targeted mutations in a genome.The efficiency of Cas9-mediated genome editing is temperature sensitive.A high-temperature regime can increase the mutation efficiency induced by the CRISPR/Cas9 system in many plant species.However,a heat stress treatment has not been applied during the tissue culture process in citrus.To develop an efficient heat stress regime to improve the efficiency of CRISPR/Cas9-mediated targeted mutagenesis,three and five cycles of heat stress treatments were used during callus induction in citrus.The results showed that the heat stress treatment with three cycles of 24 h at 37℃,followed by 24 h at 26℃,increased the mutation efficiency by 11.6%compared with no heat stress treatment,and that five cycles of heat stress treatment were optimal,from which 50%mutants had a 100%mutation rate.The mutation profiles of Cas9 at 28℃ for 10 d and 37℃ for three or five cycles were similar,indicating that heat stress treatment did not affect the non-homologous end joining repair pathway.No detectable off-target mutation was detected in the potential off-target sites with four nucleotide mismatches compared with the designed on-target site.This study demonstrated that five cycles of heat stress treatment during callus induction could efficiently increase the mutation efficiency mediated by the CRISPR/Cas9 system without observable negative effects,and provided an efficient Cas9-mediated citrus genome editing system to produce mutants with a high mutation rate.展开更多
BACKGROUND In this case report,we aimed to raise awareness regarding arrhythmogenic cardiomyopathy(ACM)with inflammatory“hot phase”episodes in pediatric patients,which is often misdiagnosed as myocarditis.This condi...BACKGROUND In this case report,we aimed to raise awareness regarding arrhythmogenic cardiomyopathy(ACM)with inflammatory“hot phase”episodes in pediatric patients,which is often misdiagnosed as myocarditis.This condition,caused by aseptic intracellular inflammation,can be misdiagnosed as acute coronary syndrome or myocardial viral infection,with the latter being particularly common in children.Here,we report two pediatric cases of ACM with“hot phase”episodes and discuss the molecular mechanisms leading to aseptic myocardial inflammation due to desmosome and cytoskeletal damage.CASE SUMMARY The first patient(aged 13 years)was hospitalized after experiencing a single episode of syncope,chest pain,and palpitation.Clinical examination revealed elevated troponin levels,complete right bundle branch block,right ventricular dilation,and normal coronary arteries.Cardiac magnetic resonance imaging(MRI)revealed extensive fibrotic changes in the right ventricle,which was consistent with ACM,and a pathogenic variant in DSG2 confirmed the diagnosis.The second patient(aged 4 years)presented with chest pain and elevated troponin levels.Electrocardiography revealed a left bundle branch block,while echocardiography showed reduced left ventricular contractility.Cardiac MRI demonstrated left ventricular dilation and subepicardial fibrosis.The phenotypic features,such as curly-wool hair,hyperkeratosis,and onychodystrophy,suggested a genetic nature of the disease.Two mutations identified in DSP confirmed the diagnosis of Carvajal syndrome with intermittent“hot phase”episodes.CONCLUSION ACM in children can present with nonspecific inflammatory symptoms,which may be misdiagnosed as myocarditis or coronary artery pathology.展开更多
基金Supported by the National Major Scientific Equipment Program(No.2012YQ12008005)
文摘We analyzed the clinical features and NF1 gene mutation in a Chinese pedigree of neurofibromatosis type 1（NF1）. Three members of this family were NF1 patients presenting with different clinical phenotypes and the others were asymptomatic. Exons of NF1 were amplified by polymerase chain reaction, sequenced, compared with a reference database. One novel NF1 frame-shift mutation c.703_704delTA, which resulted in a premature stop signal at codon 720 and the synthesis of truncated, was revealed. This mutation segregated with the NF1 members is likely responsible for the pathogenesis of NF1 in the family.
基金supported by the Fundamental Research Funds for the Central Universities of China(2572022DQ03)the National Natural Science Foundation of China(32170517)+2 种基金the Guangdong Provincial Key Laboratory of Genome Read and Write(2017B030301011)the Start-up Scientific Foundation of Northeast Forestry University(60201524043)supported by China National GeneBank(CNGB).
文摘Inbreeding increases genome homozygosity within populations,which can exacerbate inbreeding depression by exposing homozygous deleterious alleles that are responsible for declines in fitness traits.In small populations,genetic purging that occurs under the pressure of natural selection acts as an opposing force,contributing to a reduction of deleterious alleles.Both inbreeding and genetic purging are paramount in the field of conservation genomics.The Amur tiger(Panthera tigris altaica)lives in small populations in the forests of Northeast Asia and is among the most endangered animals on the planet.Using genome-wide assessment and comparison,we reveal substantially higher and more extensive inbreeding in wild Amur tigers(F_(ROH)=0.50)than in captive individuals(F_(ROH)=0.24).However,a relatively reduced number of lossof-function mutations in wild Amur tigers is observed compared to captive individuals,indicating genetic purging of inbreeding load with relatively large-effect alleles.The higher ratio of homozygous mutation load and number of fixed damaging alleles in the wild population indicates a less-efficient genetic purging,with purifying selection also contributing to this process.These findings provide valuable insights for the future conservation of Amur tigers.
文摘BACKGROUND Thrombophilia contributes to a significant increased risk of venous thromboembolism and can be either inherited or acquired.Hereditary thrombophilia may arise from various gene mutations,some of which have not even been adequately reported or poorly understood.Previous studies reported a rare and novel missense mutation in the prothrombin gene(p.Arg596Gln),known as prothrombin Belgrade.The mechanisms and therapeutic strategies associated with prothrombin Belgrade mutation have not been fully elucidated.CASE SUMMARY We present the case of a 26-year-old woman with recurrent systemic thrombosis induced by prothrombin Belgrade mutation.The patient suffered from cerebral venous sinus thrombosis that rapidly progressed to systemic thrombosis,alongside a family history of cerebral thrombosis,and no traditional risk factors or abnormal coagulation function.Whole-genome sequencing detected a novel and rare heterozygous prothrombin missense mutation,c.1787G>T(p.Arg596Gln),which was responsible for the major etiology of the systemic thrombosis.CONCLUSION This case strengthens our understanding about hereditary basis of thrombophilia and provokes considerations for therapeutic options on prothrombin Belgrade mutation.
基金Supported by the Medical Education Collaborative Innovation Fund of Jiangsu University,No.JDY2022015。
文摘BACKGROUND Through deeper understanding of targetable driver mutations in non-small-cell lung cancer(NSCLC)over the past years,some patients with driver mutations have benefited from the targeted molecular therapies.Although the anaplastic lymphoma kinase and BRAF mutations are not frequent subtypes in NSCLC,the availability of several targeted-drugs has been confirmed through a series of clinical trials.But little is clear about the proper strategy in rare BRAF G469A mutation,not to mention co-exhibition of anaplastic lymphoma kinase and BRAF G469A mutations,which is extremely rare in NSCLC.CASE SUMMARY We present a patient to stage IVA lung adenocarcinoma with coexisting echinoderm microtubule associated protein like-4 rearrangement and BRAF G469A mutation.She received several targeted drugs with unintended resistance and suffered from unbearable adverse events.CONCLUSION Due to the rarity of co-mutations,the case not only enriches the limited literature on NSCLC harbouring BRAF G469A and echinoderm microtubule associated protein like-4 mutations,but also suggests the efficacy and safety of specific multiple-drug therapy in such patients.
基金supported by the National Natural Science Foundation(82271057)the Natural Science Foundation of Hunan Province(2023JJ30818),China。
文摘Objective:Keratoconus(KC)is a progressive corneal ectasia disorder,arising from a myriad of causes including genetic predispositions,environmental factors,biomechanical influences,and inflammatory reactions.This study aims to identify potential pathogenetic gene mutations in patients with sporadic KC in the Han Chinese population.Methods:Twenty-five patients with primary KC as well as 50 unrelated population matched healthy controls,were included in this study to identify potential pathogenic gene mutations among sporadic KC patients in the Han Chinese population.Sanger sequencing and whole-exome sequencing(WES)were used to analyze mutations in the zinc finger protein 469(ZNF469)gene.Bioinformatics analysis was conducted to explore the potential role of ZNF469 in KC pathogenesis.Results:Five novel heterozygous missense variants were identified in KC patients.Among them,2 compound heterozygous variants,c.8986G>C(p.E2996Q)with c.11765A>C(p.D3922A),and c.4423C>G(p.L1475V)with c.10633G>A(p.G3545R),were determined to be possible pathogenic factors for KC.Conclusion:Mutations in the ZNF469 gene may contribute to the development of KC in the Han Chinese population.These mutation sites may provide valuable information for future genetic screening of KC patients and their families.
基金Supported by Natural Science Foundation of Shanghai,No.17ZR1431400National Key R and D Program of China,No.2017YFA0103902.
文摘Sotos syndrome is characterized by overgrowth features and is caused by alterations in the nuclear receptor binding SET domain protein 1 gene.Attentiondeficit/hyperactivity disorder(ADHD)is considered a neurodevelopment and psychiatric disorder in childhood.Genetic characteristics and clinical presentation could play an important role in the diagnosis of Sotos syndrome and ADHD.Magnetic resonance imaging(MRI)has been used to assess medical images in Sotos syndrome and ADHD.The images process is considered to display in MRI while wavelet fusion has been used to integrate distinct images for achieving more complete information in single image in this editorial.In the future,genetic mechanisms and artificial intelligence related to medical images could be used in the clinical diagnosis of Sotos syndrome and ADHD.
文摘Objective:To investigate the clinical and molecular genetic characteristics of Chinese adolescents with maturity-onset diabetes of the young type 2(MODY 2)and the safety and efficacy of recombinant human growth hormone(r-hGH).Methods:The clinical features and laboratory data of a family with MODY 2 combined with partial growth hormone deficiency(pGHD),diagnosed at the Fourth Clinical Medical College of Xinjiang Medical University,were analyzed.DNA was extracted from peripheral blood using the column method,and Sanger sequencing was conducted to analyze the glucokinase(GCK),hepatocyte nuclear factor 1α(HNF1α),and hepatocyte nuclear factor 4α(HNF4α)in the proband and relevant family members.Results:A heterozygous mutation in GCK(Reference sequence:NM_000162,location:Exon 10)c.1340G>A(p.R447Q)was detected in three family members(the proband,the proband’s younger brother,and their mother).The proband also had pGHD.Conclusion:GCK mutations causing MODY 2 exist in the Chinese population,and the combined treatment with r-hGH is safe and effective.
基金supported by the Natural Science Foundation of Fujian Province,No.2020J02027the National Natural Science Foundation of China,No.31970461the Foundation of NHC Key Laboratory of Technical Evaluation of Fertility Regulation for Non-human Primate,Fujian Maternity and Child Health Hospital,No.2022-NHP-05(all to WC).
文摘Certain amino acids changes in the human Na^(+)/K^(+)-ATPase pump,ATPase Na^(+)/K^(+)transporting subunit alpha 1(ATP1A1),cause Charcot-Marie-Tooth disease type 2(CMT2)disease and refractory seizures.To develop in vivo models to study the role of Na^(+)/K^(+)-ATPase in these diseases,we modified the Drosophila gene homolog,Atpα,to mimic the human ATP1A1 gene mutations that cause CMT2.Mutations located within the helical linker region of human ATP1A1(I592T,A597T,P600T,and D601F)were simultaneously introduced into endogenous Drosophila Atpαby CRISPR/Cas9-mediated genome editing,generating the Atpα^(TTTF)model.In addition,the same strategy was used to generate the corresponding single point mutations in flies(Atpα^(I571T),Atpα^(A576T),Atpα^(P579T),and Atpα^(D580F)).Moreover,a deletion mutation(Atpα^(mut))that causes premature termination of translation was generated as a positive control.Of these alleles,we found two that could be maintained as homozygotes(Atpα^(I571T)and Atpα^(P579T)).Three alleles(Atpα^(A576T),Atpα^(P579)and Atpα^(D580F))can form heterozygotes with the Atpαmut allele.We found that the Atpαallele carrying these CMT2-associated mutations showed differential phenotypes in Drosophila.Flies heterozygous for Atpα^(TTTF)mutations have motor performance defects,a reduced lifespan,seizures,and an abnormal neuronal morphology.These Drosophila models will provide a new platform for studying the function and regulation of the sodium-potassium pump.
基金supported by grants from the National Natural Science Foundation of China(32170238,32400191)Guangdong Basic and Applied Basic Research Foundation(2023A1515111029)+2 种基金the Science,Technology and Innovation Commission of Shenzhen Municipality(RCYX20200714114538196)the Chinese Academy of Agricultural Sciences Elite Youth Program(grant 110243160001007)the Guangdong Pearl River Talent Program(2021QN02N792)。
文摘Single-stranded DNA-binding proteins(SSBs)play essential roles in the replication,recombination and repair processes of organellar DNA molecules.In Arabidopsis thaliana,SSBs are encoded by a small family of two genes(SSB1 and SSB2).However,the functional divergence of these two SSB copies in plants remains largely unknown,and detailed studies regarding their roles in the replication and recombination of organellar genomes are still incomplete.In this study,phylogenetic,gene structure and protein motif analyses all suggested that SSB1 and SSB2 probably diverged during the early evolution of seed plants.Based on accurate long-read sequencing results,ssb1 and ssb2 mutants had decreased copy numbers for both mitochondrial DNA(mtDNA)and plastid DNA(ptDNA),accompanied by a slight increase in structural rearrangements mediated by intermediate-sized repeats in mt genome and small-scale variants in both genomes.Our findings provide an important foundation for further investigating the effects of DNA dosage in the regulation of mutation frequencies in plant organellar genomes.
文摘In renewing tissues,mutations conferring selective advantage may result in clonal expansions1-4.In contrast to somatic tissues,mutations driving clonal expansions in spermatogonia(CES)are also transmitted to the next generation.This results in an effective increase of de novo mutation rate for CES drivers5-8.CES was originally discovered through extreme recurrence of de novo mutations causing Apert syndrome5.Here,we develop a systematic approach to discover CES drivers as hotspots of human de novo mutation.Our analysis of 54,715 trios ascertained for rare conditions9-13,6,065 control trios12,14-19 and population variation from 807,162 mostly healthy individuals20 identifies genes manifesting rates of de novo mutations inconsistent with plausible models of disease ascertainment.We propose 23 genes hypermutable at loss-of-function(LoF)sites as candidate CES drivers.An extra 17 genes feature hypermutable missense mutations at individual positions,suggesting CES acting through gain of function.CES increases the average mutation rate roughly 17-fold for LoF genes in both control trios and sperm and roughly 500-fold for pooled gain-of-function sites in sperm21.Positive selection in the male germline elevates the prevalence of genetic disorders and increases polymorphism levels,masking the effect of negative selection in human populations.
文摘Imagine a future where a single vaccine could protect you from a multitude of influenza strains,offering broad immunity with minimal risk.This vision is now closer to reality,thanks to a recent study that harnesses the power of cellular proteins to create a new generation of live attenuated vaccines that outsmart flu’s relentless mutations.
基金supported by the National Natural Science Foundation of China(grant no.82272891).
文摘As the study of vascular anomalies progresses,it is imperative for plastic surgeons to individualize their in-depth research and practice to develop more effective and personalized treatment plans.Recent advancements in genome sequencing technology have highlighted the importance of vascular endothelial growth factor(VEGF)and its receptor(VEGFR)in the formation and alteration of vascularity.However,definitive reports regarding mutations associated with this locus and treatment experiences remain scarce.Herein,we report a clinical case of multiple venous malformations with mutations in VEGFR3(FLT4).We implemented a comprehensive approach,including local lesion excision of the left foot and trunk,oral propranolol administration,and local physiotherapy.After two years of follow-up,the patient’s left foot venous malformation did not recur,and he expressed satisfaction with the outcomes of the combined therapy.This case offers valuable insights into the clinical management of this mutant type and similar presentations of multiple venous malformations.
基金supported by Decit/SCTIE-Ministério da Saúde,Conselho Nacional de Desenvolvimento Científico e Tecnológico(CNPq),Fundação de AmparoàPesquisa do Estado de Alagoas(FAPEAL)and Secretaria de Estado da Saúde de Alagoas(SESAU-AL)[PPSUS 60030000841/2016].
文摘Objective:To investigate mutations in the Chikungunya(CHIKV)envelope genome region and evaluate their potential impact on B lymphocyte epitopes via in silico analysis.Methods:E1,E2 and 6K protein genes were sequenced from viral RNA isolated from 13 CHIKV-positive serum samples from Alagoas State,Brazil,during the 2016 outbreak.Phylogenetic analysis,experimental epitope identification in the immune epitope database(IEDB)and in silico approaches were employed to predict the potential impact of the detected mutations.Results:The sequences were clustered via phylogenetic analysis.The CHIKV isolates belong to the ECSA genotype,with 13 detected amino acid mutations.Five mutations are located on the surface of the viral particle in regions critical for cellular receptor interaction.Nine mutations are known experimentally validated epitopes for B and T cells.In B-cell epitope predictions,mutations affect sequences within three conformational epitopes in E2 and one in E1,as well as linear epitopes.Notably,the E2-G60D mutation found in the Alagoas strain has been previously reported to influence the vector competence of Aedes aegypti,the primary vector in Brazil.Conclusions:Genomic surveillance and an in-depth understanding of viral mutations are crucial for adapting public health strategies and improving the outbreak response.These findings could have significant public health implications,such as the development of more effective vaccines,diagnostic tests,and antiviral therapies.
基金funded by the National Natural Science Foundation of China(32372585)the Natural Science Foundation of Jiangsu Province,China(BK20231471)the National Training Program of Innovation and Entrepreneurship for Undergraduates,China(202210307013Z)。
文摘The use of RNA interference(RNAi)technology to control pests is explored by researchers globally.Even though RNA is a new class of pest control compound unlike conventional chemical pesticides,the evolution of pest resistance needs to be considered.Here,we first investigate RNAi-based biopesticide resistance of Fusarium asiaticum,which is responsible for devastating diseases of plants,for example,Fusarium head blight.Five resistant strains were isolated from 500 strains that treated with UV-mutagenesis.The mutation common to all of the five resistant mutants occurred in the gene encoding Dicer2(point mutations at codon 1005 and 1007),which were under strong purifying selection pressure.To confirm whether the mutations in Dicer2 confer resistance to RNAi,we exchanged the Dicer2 locus between the sensitive strain and the resistant strain by homologous double exchange.The transformed mutants,Dicer2^(R1005D)and Dicer2^(E1007H),exhibited resistance to dsRNA in vitro.Further study showed that mutations of R1005D and E1007H affected the intramolecular interactions of Dicer2,resulting in the dysfunction of RNase III domain of Dicer2.The amount of sRNAs produced by Dicer2^(R1005D)and Dicer2^(E1007H)was extremely reduced along with variation of sRNA length.Together,these findings revealed a new potential mechanism of RNAi resistance and provided insight into RNAi-related biopesticide deployment for fungal control.
文摘Dear Editor,Mutations in genomic sequences exhibit a strong correlation with various pathological processes of cancers[1].Currently,the next-generation sequencing technique[2]and polymerase chain reaction(PCR)were the established benchmarks for analyzing DNA mutations.However,the two methods necessitate intricate experimental preparation,costly instrumentation,and skilled personnel,making them challenging for rapid mutations analysis.More importantly,these methods lack adequate accuracy for one base mutations analysis[3].Therefore,the development of a reliable and exceptionally sensitive mutation analysis approach holds immense importance in cancer diagnosis and treatment.
基金Supported by the National Key Research and Development Program of China(No.2022ZD0119001)。
文摘The honey badger algorithm(HBA),as a new swarm intelligence(SI)optimization algorithm,has shown certain effectiveness in its applications.Aiming at the problems of unsatisfactory initial population distribution of HBA,poor ability to avoid local optimum,and slow convergence speed,this paper proposes a multi-strategy improved HBA based on periodical mutation and t-distribution perturbation,called MHBA.Firstly,a good point set population initialization is introduced to get a uniform initial population.Secondly,periodic mutation and t-distribution perturbation are successively used to improve the algorithm’s ability to avoid local optimum.Finally,the density factor is improved for balancing exploration and exploitation.By comparing MHBA with HBA and 7 other SIs on 6 benchmark functions,it is evident that the performance of MHBA is far superior to HBA.In addition,by applying MHBA to robot path planning,MHBA can identify the shortest path more quickly and consistently compared with competitors.
基金supported by the Jilin Provincial Department of Education Science and Technology Research Project(JJKH20231141K)Natural Science Foundation of Jilin Province of China(20230101154JC)Young Elite Scientists Sponsorship Program by CAST(2022QNRC001)。
文摘Chronic pancreatitis(CP)is a progressive and irreversible fibroinflammatory disease that markedly increases susceptibility to pancreatic cancer and remains without effective targeted therapies.Among the genetic contributors to CP,the carboxypeptidase A1 p.Ser282Pro(CPA1^(S282P))variant has been proposed to promote disease through misfolding-induced endoplasmic reticulum stress(ERS),although the broader pathogenic landscape remains incompletely defined.This study generated a rabbit model mimicking the human CPA1S282P mutation using the SpRY-ABE-8.17 system.Homozygous CPA1^(S282P)rabbits exhibited characteristic human CP phenotypes following alcohol induction,including visceral pain,elevated serum lipase and amylase,inflammatory cell infiltration,and extensive pancreatic fibrosis.Biochemical analyses confirmed that the p.S282P mutation induced CPA1 misfolding and elevated the expression of ERS markers GRP78 and CHOP in both transfected HEK293T cells and homozygous mutant rabbits.Notably,the CPA1^(S282P)mutation markedly disrupted intra-pancreatic lipid homeostasis,contributing to the development of CP in mutant rabbits.This study successfully established the first rabbit model of CP that accurately recapitulates CP caused by a defined human point mutation.Additionally,this study provides insights into a previously unrecognized link between CPA1 and intra-pancreatic lipid metabolism,offering a foundation for identifying novel therapeutic targets for human CP.
基金Supported by Clinical Research Center for Precision Medicine of Abdominal Tumor of Fujian Province.
文摘BACKGROUND Pancreatic cancer(PC)is a highly malignant tumor that is resistant to chemotherapy,radiotherapy and immunotherapy.Combination chemotherapy regimens are the standard first-line regimens for metastatic disease,with a median survival<12 months.Although recurrent genomic alterations such as the BRAF V600E mutation have been reported in PC,evidence supporting the clinical effectiveness of molecularly guided targeted therapies is limited.CASE SUMMARY We report a case of a 33-year-old male who was referred to our department with weight loss of 5 kg in 2 months,anorexia and abdominal pain.Imaging showed extensive lesions involving the pancreas,liver,bones,muscles and lymph nodes accompanied by elevated carbohydrate antigen 19-9(CA19-9)and carcinoembryonic antigen(CEA).Biopsy yielded a diagnosis of PC.Treatment with gemcitabine and nab-paclitaxel was initiated,but the disease progressed in<2 months even though the patient’s general condition improved.Molecular testing revealed the presence of BRAF mutation.Dabrafenib/trametinib combination therapy was introduced,and the patient was treated for 2 months with a decrease in CA19-9 and CEA levels,but he died after 2 months of treatment.CONCLUSION BRAF alterations are infrequent in PC.This case highlights the significance of molecular profiling in patients with PC,especially in patients with a high tumor burden.
基金supported by the National Key Research and Development Program of China(Grant No.2022YFD1201600)Earmarked Fund for China Agriculture Research System(Grant No.CARS-26)+1 种基金Chongqing Natural Science Foundation Project(Grant No.CSTB2023NSCQ-MSX1085)Cultivar Improvement of Nanfeng Orange.
文摘The CRISPR/Cas9 system has shown great promise in engineering targeted mutations in a genome.The efficiency of Cas9-mediated genome editing is temperature sensitive.A high-temperature regime can increase the mutation efficiency induced by the CRISPR/Cas9 system in many plant species.However,a heat stress treatment has not been applied during the tissue culture process in citrus.To develop an efficient heat stress regime to improve the efficiency of CRISPR/Cas9-mediated targeted mutagenesis,three and five cycles of heat stress treatments were used during callus induction in citrus.The results showed that the heat stress treatment with three cycles of 24 h at 37℃,followed by 24 h at 26℃,increased the mutation efficiency by 11.6%compared with no heat stress treatment,and that five cycles of heat stress treatment were optimal,from which 50%mutants had a 100%mutation rate.The mutation profiles of Cas9 at 28℃ for 10 d and 37℃ for three or five cycles were similar,indicating that heat stress treatment did not affect the non-homologous end joining repair pathway.No detectable off-target mutation was detected in the potential off-target sites with four nucleotide mismatches compared with the designed on-target site.This study demonstrated that five cycles of heat stress treatment during callus induction could efficiently increase the mutation efficiency mediated by the CRISPR/Cas9 system without observable negative effects,and provided an efficient Cas9-mediated citrus genome editing system to produce mutants with a high mutation rate.
基金Supported by Russian Science Foundation,No.24-15-20026/12.04.2024St.Petersburg Research Foundation,No.24-15-20026/24.05.2024.
文摘BACKGROUND In this case report,we aimed to raise awareness regarding arrhythmogenic cardiomyopathy(ACM)with inflammatory“hot phase”episodes in pediatric patients,which is often misdiagnosed as myocarditis.This condition,caused by aseptic intracellular inflammation,can be misdiagnosed as acute coronary syndrome or myocardial viral infection,with the latter being particularly common in children.Here,we report two pediatric cases of ACM with“hot phase”episodes and discuss the molecular mechanisms leading to aseptic myocardial inflammation due to desmosome and cytoskeletal damage.CASE SUMMARY The first patient(aged 13 years)was hospitalized after experiencing a single episode of syncope,chest pain,and palpitation.Clinical examination revealed elevated troponin levels,complete right bundle branch block,right ventricular dilation,and normal coronary arteries.Cardiac magnetic resonance imaging(MRI)revealed extensive fibrotic changes in the right ventricle,which was consistent with ACM,and a pathogenic variant in DSG2 confirmed the diagnosis.The second patient(aged 4 years)presented with chest pain and elevated troponin levels.Electrocardiography revealed a left bundle branch block,while echocardiography showed reduced left ventricular contractility.Cardiac MRI demonstrated left ventricular dilation and subepicardial fibrosis.The phenotypic features,such as curly-wool hair,hyperkeratosis,and onychodystrophy,suggested a genetic nature of the disease.Two mutations identified in DSP confirmed the diagnosis of Carvajal syndrome with intermittent“hot phase”episodes.CONCLUSION ACM in children can present with nonspecific inflammatory symptoms,which may be misdiagnosed as myocarditis or coronary artery pathology.
