Uric acid is the end product of purine catabolism and its plasma levels are maintained below its maximum solubility in water(6–7 mg/dl).The plasma levels are tightly regulated as the balance between the rate of produ...Uric acid is the end product of purine catabolism and its plasma levels are maintained below its maximum solubility in water(6–7 mg/dl).The plasma levels are tightly regulated as the balance between the rate of production and the rate of excretion,the latter occurring in urine(kidney),bile(liver)and feces(intestinal tract).Reabsorption in kidney is also an important component of this process.Both excretion and reabsorption are mediated by specific transporters.Disruption of the balance between production and excretion leads to hyperuricemia,which increases the risk of uric acid crystallization as monosodium urate with subsequent deposition of the crystals in joints causing gouty arthritis.Loss-of-function mutations in the transporters that mediate uric acid excretion are associated with gout.The ATP-Binding Cassette exporter ABCG2 is important in uric acid excretion at all three sites:kidney(urine),liver(bile),and intestine(feces).Mutations in this transporter cause gout and these mutations occur at significant prevalence in general population.However,mutations that are most prevalent result only in partial loss of transport function.Therefore,if the expression of these partially defective transporters could be induced,the increased number of the transporter molecules would compensate for the mutation-associated decrease in transport function and hence increase uric acid excretion.As such,pharmacologic agents with ability to induce the expression of ABCG2 represent potentially a novel class of drugs for treatment of gouty arthritis.展开更多
KCNA1 is the coding gene for Kv1.1 voltage-gated potassium-channelαsubunit.Three variants of KCNA1 have been reported to manifest as paroxysmal kinesigenic dyskinesia(PKD),but the correlation between them remains unc...KCNA1 is the coding gene for Kv1.1 voltage-gated potassium-channelαsubunit.Three variants of KCNA1 have been reported to manifest as paroxysmal kinesigenic dyskinesia(PKD),but the correlation between them remains unclear due to the phenotypic complexity of KCNA1 variants as well as the rarity of PKD cases.Using the whole exome sequencing followed by Sanger sequencing,we screen for potential pathogenic KCNA1 variants in patients clinically diagnosed with paroxysmal movement disorders and identify three previously unreported missense variants of KCNA1 in three unrelated Chinese families.The proband of one family(c.496G>A,p.A166T)manifests as episodic ataxia type 1,and the other two(c.877G>A,p.V293I and c.1112C>A,p.T371A)manifest as PKD.The pathogenicity of these variants is confirmed by functional studies,suggesting that p.A166T and p.T371A cause a loss-of-function of the channel,while p.V293I leads to a gain-of-function with the property of voltage-dependent gating and activation kinetic affected.By reviewing the locations of PKD-manifested KCNA1 variants in Kv1.1 protein,we find that these variants tend to cluster around the pore domain,which is similar to epilepsy.Thus,our study strengthens the correlation between KCNA1 variants and PKD and provides more information on genotype–phenotype correlations of KCNA1 channelopathy.展开更多
The ability to precisely inactivate or modify genes in model organisms helps us understand the mysteries of life. Clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein 9(Cas9), a ...The ability to precisely inactivate or modify genes in model organisms helps us understand the mysteries of life. Clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein 9(Cas9), a revolutionary technology that could generate targeted mutants, has facilitated notable advances in plant science. Genome editing with CRISPR/Cas9 has gained great popularity and enabled several technical breakthroughs. Herein, we briefly introduce the CRISPR/Cas9, with a focus on the latest breakthroughs in precise genome editing(e.g., base editing and prime editing), and we summarize various platforms that developed to increase the editing efficiency, expand the targeting scope, and improve the specificity of base editing in plants. In addition, we emphasize the recent applications of these technologies to plants. Finally, we predict that CRISPR/Cas9 and CRISPR/Cas9-based genome editing will continue to revolutionize plant science and provide technical support for sustainable agricultural development.展开更多
Orofacial clefts (OFCs) are the most common congenital craniofacial disorders, of which the etiology is closely related to rare coding variants. Filamin B (FLNB) is an actin-binding protein implicated in bone formatio...Orofacial clefts (OFCs) are the most common congenital craniofacial disorders, of which the etiology is closely related to rare coding variants. Filamin B (FLNB) is an actin-binding protein implicated in bone formation. FLNB mutations have been identified in several types of syndromic OFCs and previous studies suggest a role of FLNB in the onset of non-syndromic OFCs (NSOFCs). Here, we report two rare heterozygous variants (p.P441T and p.G565R) in FLNB in two unrelated hereditary families with NSOFCs. Bioinformatics analysis suggests that both variants may disrupt the function of FLNB. In mammalian cells, p.P441T and p.G565R variants are less potent to induce cell stretches than wild type FLNB, suggesting that they are loss-of-function mutations. Immunohistochemistry analysis demonstrates that FLNB is abundantly expressed during palatal development. Importantly, Flnb^(−/−) embryos display cleft palates and previously defined skeletal defects. Taken together, our findings reveal that FLNB is required for development of palates in mice and FLNB is a bona fide causal gene for NSOFCs in humans.展开更多
T-box transcription factor T(TBXT;T)is required for mesodermal formation and axial skeletal development.Although it has been extensively studied in various model organisms,human congenital vertebral malformations(CVMs...T-box transcription factor T(TBXT;T)is required for mesodermal formation and axial skeletal development.Although it has been extensively studied in various model organisms,human congenital vertebral malformations(CVMs)involving T are not well established.Here,we report a family with 15 CVM patients distributed across 4 generations.All affected individuals carry a heterozygous mutation,T c.596A>G(p.Q199R),which is not found in unaffected family members,indicating co-segregation of the genotype and phenotype.In vitro assays show that T p.Q199R increases the nucleocytoplasmic ratio and enhances its DNA-binding affinity,but reduces its transcriptional activity compared to the wild-type.To determine the pathogenicity of this mutation in vivo,we generated a Q199R knock-in mouse model that recapitulates the human CVM phenotype.Most heterozygous Q199R mice show subtle kinked or shortened tails,while homozygous mice exhibit tail filaments and severe vertebral deformities.Overall,we show that the Q199R mutation in T causes CVM in humans and mice,providing previously unreported evidence supporting the function of T in the genetic etiology of human CVM.展开更多
Gene gain and loss are crucial factors that shape the evolutionary success of diverse organisms.In the past two decades,more attention has been paid to the significance of gene gain through gene duplication or de novo...Gene gain and loss are crucial factors that shape the evolutionary success of diverse organisms.In the past two decades,more attention has been paid to the significance of gene gain through gene duplication or de novo genes.However,gene loss through natural loss-of-function(LoF)mutations,which isprevalent in the genomes of diverse organisms,has been largely ignored.With the development of sequencing techniques,many genomes have been sequenced across diverse species and can be used to study the evolutionary patterns of gene loss.In this review,we summarize recent advances in research on various aspects of LoF mutations,including their identification,evolutionary dynamics in natural populations,and functional effects.In particular,we discuss how LoF mutations can provide insights into the minimum gene set(or the essential gene set)of an organism.Furthermore,we emphasize their potential impact on adaptation.At the genome level,although most LoF mutations are neutral or deleterious,at least some of them are under positive selection and may contribute to biodiversity and adaptation.Overall,we highlight the importance of natural LoF mutations as a robust framework for understanding biological questions in general.展开更多
Male infertility is a major reproductive disorder,which is clinically characterized by highly heterogeneous phenotypes of abnormal sperm count or quality.To date,five male patients with biallelic loss-of-function(LOF)...Male infertility is a major reproductive disorder,which is clinically characterized by highly heterogeneous phenotypes of abnormal sperm count or quality.To date,five male patients with biallelic loss-of-function(LOF)variants of PARN-like ribonuclease domain-containing exonuclease 1(PNLDC1)have been reported to experience infertility with nonobstructive azoospermia.The aim of this study was to identify the genetic cause of male infertility with oligo-astheno-teratozoospermia(OAT)in a patient from a Chinese Han family.Whole-exome and Sanger sequencing analyses identified a homozygous LOF variant(NM_173516.2,c.l42C>T,p.Gln48Ter)in PNLDC1.Hematoxylin and eosin staining revealed that the spermatozoa of the patient with OAT had an irregular head phenotype,including microcephaly,head tapering,and globozoospermia.Consistently,peanut agglutinin staining of the spermatozoa revealed a complete or partial loss of the acrosome.Furthermore,the disomy rate of chromosomes in the patient’s spermatozoa was significantly increased compared with that of a fertile control sample.We reported an LOF variant of the PNLDC1 gene responsible for OAT.展开更多
Hepatocellular carcinoma(HCC)is a very deadly disease.HCC initiation and progression involve multiple genetic events,including the activation of proto-oncogenes and disruption of the function of specific tumor suppres...Hepatocellular carcinoma(HCC)is a very deadly disease.HCC initiation and progression involve multiple genetic events,including the activation of proto-oncogenes and disruption of the function of specific tumor suppressor genes.Activation of oncogenes stimulates cell growth and survival,while loss-of-function mutations of tumor suppressor genes result in unrestrained cell growth.In this review,we summarize the new findings that identified novel proto-oncogenes and tumor suppressors in HCC over the past five years.These findings may inspire the development of novel therapeutic strategies to improve the outcome of HCC patients.展开更多
We have known since 1976 that cancer evolves clonally from one initiated<span style="font-family:;" "=""><span> normal human cell, the </span><i><span>first cell&...We have known since 1976 that cancer evolves clonally from one initiated<span style="font-family:;" "=""><span> normal human cell, the </span><i><span>first cell</span></i><span>. Today we see that this fact has been overshadowed from federal funding choice of the mutation theory (MT), which not yet has shown tumorigenesis-initiation in normal human cells. Our suggested, death signaled, stress model from time delayed S-period (replication slowness), causing repair instability from under-replicated lesions in repetitive DNAs, herein has the objective of revealing, significant literature support from a mini-review. We reasoned that early versus late S-period stress would </span><span>have different outcomes: early the slowness affecting mitotic slippage with</span> <span>diploid re-replication to 4n cells whereas late-S, with milder stress effect,</span><span> pro</span><span>ducing diploid cells. In cancer burden, near-half is diploid, but tetraploid</span><span> solid tumors have the attention. The initial 4n cells were special with orderly genomic reductive division to diploid first cells with measurable fitness-gain from hours-reduced total cell cycle time. Experimental data from Coxsakie-B3 virus infected normal fibroblasts, reiterated 4n cell production from </span><span>death-s</span><span>ignaled recovery-cells with progressive cell-phenotypic changes to polygon</span><span>al </span><span>and roundness cell-shapes, indistinguishable from diagnostic/prognostic </span><span>cancer </span><span>morphology. The 4n cells showed a self-inflicted 90</span></span><span style="font-family:;" "=""><span><span style="color:#4F4F4F;white-space:normal;background-color:#FFFFFF;"><span style="color:#4F4F4F;white-space:normal;background-color:#FFFFFF;">°</span></span></span><span> turn of the 4n nucleus</span></span><span style="font-family:;" "=""> <span>before division, affecting a perpendicular orientation of the fitness-gained</span><span> first cells relative to neighboring cells. In an illustrated cell cycle drawin展开更多
A spontaneously occurred rice ( Oryza sativa L.) mutant characterized by homeotic conversions in glumes and stamens was found in the progeny of a breeding material. The mutant plant shows degenerated glumes and mor...A spontaneously occurred rice ( Oryza sativa L.) mutant characterized by homeotic conversions in glumes and stamens was found in the progeny of a breeding material. The mutant plant shows degenerated glumes and morphological transformation of stamens into pistils. A mutant floret consists of 1 to 3 completely developed pistils and 4 to 6 incomplete pistils with no ovary. Some pistilloid stamens still have filaments but tipped by bulged tissue and 0 to 3 stigmas. Three ovaries in a single floret were observed in its cross and longitudinal sections. When the mutant plants were pollinated with pollens from wild type plants, one or two naked seeds instead of a caryopsis could be produced in a single floret. The mutant is controlled by a single recessive gene since its F 1 hybrid plants were restored to wild type and 3∶1 ratio of wild type to mutant plants were observed in the progeny of heterozygotes. It seems that the mutant phenotype of the homeotic conversions in glumes and stamens is similar to that of the B loss_of_function mutants in Arabidopsis and Antirrhinum .展开更多
基金This work was supported by the National Institutes of Health grant R41 AR074854the Welch Endowed Chair in Biochemistry,Grant No.BI-0028,at Texas Tech University Health Sciences Center.
文摘Uric acid is the end product of purine catabolism and its plasma levels are maintained below its maximum solubility in water(6–7 mg/dl).The plasma levels are tightly regulated as the balance between the rate of production and the rate of excretion,the latter occurring in urine(kidney),bile(liver)and feces(intestinal tract).Reabsorption in kidney is also an important component of this process.Both excretion and reabsorption are mediated by specific transporters.Disruption of the balance between production and excretion leads to hyperuricemia,which increases the risk of uric acid crystallization as monosodium urate with subsequent deposition of the crystals in joints causing gouty arthritis.Loss-of-function mutations in the transporters that mediate uric acid excretion are associated with gout.The ATP-Binding Cassette exporter ABCG2 is important in uric acid excretion at all three sites:kidney(urine),liver(bile),and intestine(feces).Mutations in this transporter cause gout and these mutations occur at significant prevalence in general population.However,mutations that are most prevalent result only in partial loss of transport function.Therefore,if the expression of these partially defective transporters could be induced,the increased number of the transporter molecules would compensate for the mutation-associated decrease in transport function and hence increase uric acid excretion.As such,pharmacologic agents with ability to induce the expression of ABCG2 represent potentially a novel class of drugs for treatment of gouty arthritis.
基金supported by grants from the National Natural Science Foundation of China(82101526,82171238,and 81330025)。
文摘KCNA1 is the coding gene for Kv1.1 voltage-gated potassium-channelαsubunit.Three variants of KCNA1 have been reported to manifest as paroxysmal kinesigenic dyskinesia(PKD),but the correlation between them remains unclear due to the phenotypic complexity of KCNA1 variants as well as the rarity of PKD cases.Using the whole exome sequencing followed by Sanger sequencing,we screen for potential pathogenic KCNA1 variants in patients clinically diagnosed with paroxysmal movement disorders and identify three previously unreported missense variants of KCNA1 in three unrelated Chinese families.The proband of one family(c.496G>A,p.A166T)manifests as episodic ataxia type 1,and the other two(c.877G>A,p.V293I and c.1112C>A,p.T371A)manifest as PKD.The pathogenicity of these variants is confirmed by functional studies,suggesting that p.A166T and p.T371A cause a loss-of-function of the channel,while p.V293I leads to a gain-of-function with the property of voltage-dependent gating and activation kinetic affected.By reviewing the locations of PKD-manifested KCNA1 variants in Kv1.1 protein,we find that these variants tend to cluster around the pore domain,which is similar to epilepsy.Thus,our study strengthens the correlation between KCNA1 variants and PKD and provides more information on genotype–phenotype correlations of KCNA1 channelopathy.
基金financially supported by the National Natural Science Foundation of China (32000454)Provincial Natural Science Foundation of Hebei for Excellent Young Scholar (C2020204062)+1 种基金Program for Young Talents of Hebei Education Department (BJ2021025)Starting Grant from Hebei Agricultural University (YJ201958)。
文摘The ability to precisely inactivate or modify genes in model organisms helps us understand the mysteries of life. Clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein 9(Cas9), a revolutionary technology that could generate targeted mutants, has facilitated notable advances in plant science. Genome editing with CRISPR/Cas9 has gained great popularity and enabled several technical breakthroughs. Herein, we briefly introduce the CRISPR/Cas9, with a focus on the latest breakthroughs in precise genome editing(e.g., base editing and prime editing), and we summarize various platforms that developed to increase the editing efficiency, expand the targeting scope, and improve the specificity of base editing in plants. In addition, we emphasize the recent applications of these technologies to plants. Finally, we predict that CRISPR/Cas9 and CRISPR/Cas9-based genome editing will continue to revolutionize plant science and provide technical support for sustainable agricultural development.
基金supported by the National Natural Science Foundation of China(No.81870747,82170916,81900984,and 82001030)the Fundamental Research Funds for the Central Universities(PKU2022XGK001)+2 种基金Natural Science Foundation of Beijing Municipality(7182184)Xi'an“Science and Technology+”Action Plan-Medical Research Project(20YXYJ0010[1])the Fundamental Research Funds for the Central Universities(xzy012020110).
文摘Orofacial clefts (OFCs) are the most common congenital craniofacial disorders, of which the etiology is closely related to rare coding variants. Filamin B (FLNB) is an actin-binding protein implicated in bone formation. FLNB mutations have been identified in several types of syndromic OFCs and previous studies suggest a role of FLNB in the onset of non-syndromic OFCs (NSOFCs). Here, we report two rare heterozygous variants (p.P441T and p.G565R) in FLNB in two unrelated hereditary families with NSOFCs. Bioinformatics analysis suggests that both variants may disrupt the function of FLNB. In mammalian cells, p.P441T and p.G565R variants are less potent to induce cell stretches than wild type FLNB, suggesting that they are loss-of-function mutations. Immunohistochemistry analysis demonstrates that FLNB is abundantly expressed during palatal development. Importantly, Flnb^(−/−) embryos display cleft palates and previously defined skeletal defects. Taken together, our findings reveal that FLNB is required for development of palates in mice and FLNB is a bona fide causal gene for NSOFCs in humans.
基金supported by the National Key R&D Program of China(2021YFC2701101 to H.W.and X.Y.)the National Natural Science Foundation of China(81930036 and 82150008 to H.W.,and 31000542 to X.Y.)the Commission of Science and Technology of Shanghai Municipality(20JC1418500 to H.W.).
文摘T-box transcription factor T(TBXT;T)is required for mesodermal formation and axial skeletal development.Although it has been extensively studied in various model organisms,human congenital vertebral malformations(CVMs)involving T are not well established.Here,we report a family with 15 CVM patients distributed across 4 generations.All affected individuals carry a heterozygous mutation,T c.596A>G(p.Q199R),which is not found in unaffected family members,indicating co-segregation of the genotype and phenotype.In vitro assays show that T p.Q199R increases the nucleocytoplasmic ratio and enhances its DNA-binding affinity,but reduces its transcriptional activity compared to the wild-type.To determine the pathogenicity of this mutation in vivo,we generated a Q199R knock-in mouse model that recapitulates the human CVM phenotype.Most heterozygous Q199R mice show subtle kinked or shortened tails,while homozygous mice exhibit tail filaments and severe vertebral deformities.Overall,we show that the Q199R mutation in T causes CVM in humans and mice,providing previously unreported evidence supporting the function of T in the genetic etiology of human CVM.
基金supported by the National Natural Science Foundation of China(31925004)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB27010305)the Innovative Academy of Seed Design,Chinese Academy of Sciences.
文摘Gene gain and loss are crucial factors that shape the evolutionary success of diverse organisms.In the past two decades,more attention has been paid to the significance of gene gain through gene duplication or de novo genes.However,gene loss through natural loss-of-function(LoF)mutations,which isprevalent in the genomes of diverse organisms,has been largely ignored.With the development of sequencing techniques,many genomes have been sequenced across diverse species and can be used to study the evolutionary patterns of gene loss.In this review,we summarize recent advances in research on various aspects of LoF mutations,including their identification,evolutionary dynamics in natural populations,and functional effects.In particular,we discuss how LoF mutations can provide insights into the minimum gene set(or the essential gene set)of an organism.Furthermore,we emphasize their potential impact on adaptation.At the genome level,although most LoF mutations are neutral or deleterious,at least some of them are under positive selection and may contribute to biodiversity and adaptation.Overall,we highlight the importance of natural LoF mutations as a robust framework for understanding biological questions in general.
基金supported by grants from the National Key Research and Development Program of China(2022YFC2702604)the National Natural Science Foundation of China(82171608,82201773,and 81971447)+1 种基金the China Postdoctoral Science Foundation(2022M711119)the Scientific Research Foundation of the Health Committee of Hunan Province(B202301039323 and B202301039518).
文摘Male infertility is a major reproductive disorder,which is clinically characterized by highly heterogeneous phenotypes of abnormal sperm count or quality.To date,five male patients with biallelic loss-of-function(LOF)variants of PARN-like ribonuclease domain-containing exonuclease 1(PNLDC1)have been reported to experience infertility with nonobstructive azoospermia.The aim of this study was to identify the genetic cause of male infertility with oligo-astheno-teratozoospermia(OAT)in a patient from a Chinese Han family.Whole-exome and Sanger sequencing analyses identified a homozygous LOF variant(NM_173516.2,c.l42C>T,p.Gln48Ter)in PNLDC1.Hematoxylin and eosin staining revealed that the spermatozoa of the patient with OAT had an irregular head phenotype,including microcephaly,head tapering,and globozoospermia.Consistently,peanut agglutinin staining of the spermatozoa revealed a complete or partial loss of the acrosome.Furthermore,the disomy rate of chromosomes in the patient’s spermatozoa was significantly increased compared with that of a fertile control sample.We reported an LOF variant of the PNLDC1 gene responsible for OAT.
文摘Hepatocellular carcinoma(HCC)is a very deadly disease.HCC initiation and progression involve multiple genetic events,including the activation of proto-oncogenes and disruption of the function of specific tumor suppressor genes.Activation of oncogenes stimulates cell growth and survival,while loss-of-function mutations of tumor suppressor genes result in unrestrained cell growth.In this review,we summarize the new findings that identified novel proto-oncogenes and tumor suppressors in HCC over the past five years.These findings may inspire the development of novel therapeutic strategies to improve the outcome of HCC patients.
文摘We have known since 1976 that cancer evolves clonally from one initiated<span style="font-family:;" "=""><span> normal human cell, the </span><i><span>first cell</span></i><span>. Today we see that this fact has been overshadowed from federal funding choice of the mutation theory (MT), which not yet has shown tumorigenesis-initiation in normal human cells. Our suggested, death signaled, stress model from time delayed S-period (replication slowness), causing repair instability from under-replicated lesions in repetitive DNAs, herein has the objective of revealing, significant literature support from a mini-review. We reasoned that early versus late S-period stress would </span><span>have different outcomes: early the slowness affecting mitotic slippage with</span> <span>diploid re-replication to 4n cells whereas late-S, with milder stress effect,</span><span> pro</span><span>ducing diploid cells. In cancer burden, near-half is diploid, but tetraploid</span><span> solid tumors have the attention. The initial 4n cells were special with orderly genomic reductive division to diploid first cells with measurable fitness-gain from hours-reduced total cell cycle time. Experimental data from Coxsakie-B3 virus infected normal fibroblasts, reiterated 4n cell production from </span><span>death-s</span><span>ignaled recovery-cells with progressive cell-phenotypic changes to polygon</span><span>al </span><span>and roundness cell-shapes, indistinguishable from diagnostic/prognostic </span><span>cancer </span><span>morphology. The 4n cells showed a self-inflicted 90</span></span><span style="font-family:;" "=""><span><span style="color:#4F4F4F;white-space:normal;background-color:#FFFFFF;"><span style="color:#4F4F4F;white-space:normal;background-color:#FFFFFF;">°</span></span></span><span> turn of the 4n nucleus</span></span><span style="font-family:;" "=""> <span>before division, affecting a perpendicular orientation of the fitness-gained</span><span> first cells relative to neighboring cells. In an illustrated cell cycle drawin
文摘A spontaneously occurred rice ( Oryza sativa L.) mutant characterized by homeotic conversions in glumes and stamens was found in the progeny of a breeding material. The mutant plant shows degenerated glumes and morphological transformation of stamens into pistils. A mutant floret consists of 1 to 3 completely developed pistils and 4 to 6 incomplete pistils with no ovary. Some pistilloid stamens still have filaments but tipped by bulged tissue and 0 to 3 stigmas. Three ovaries in a single floret were observed in its cross and longitudinal sections. When the mutant plants were pollinated with pollens from wild type plants, one or two naked seeds instead of a caryopsis could be produced in a single floret. The mutant is controlled by a single recessive gene since its F 1 hybrid plants were restored to wild type and 3∶1 ratio of wild type to mutant plants were observed in the progeny of heterozygotes. It seems that the mutant phenotype of the homeotic conversions in glumes and stamens is similar to that of the B loss_of_function mutants in Arabidopsis and Antirrhinum .
