The bivariate interpolation in two dimensional space R2 is more complicated than that in one dimensional space R, because there is no Haar space of continuous functions in R2. Therefore, the bivariate interpolation ha...The bivariate interpolation in two dimensional space R2 is more complicated than that in one dimensional space R, because there is no Haar space of continuous functions in R2. Therefore, the bivariate interpolation has not a unique solution for a set of arbitrary distinct pairwise points. In this work, we suggest a type of basis which depends on the points such that the bivariate interpolation has the unique solution for any set of distinct pairwise points. In this case, the matrix of bivariate interpolation has the semi inherited factorization.展开更多
Familial intrahepatic cholestasis(FIC) comprises a group of rare cholestatic liver diseases associated with canalicular transport defects resulting predominantly from mutations in ATP8B1, ABCB11 and ABCB4. Phe-notypes...Familial intrahepatic cholestasis(FIC) comprises a group of rare cholestatic liver diseases associated with canalicular transport defects resulting predominantly from mutations in ATP8B1, ABCB11 and ABCB4. Phe-notypes range from benign recurrent intrahepatic cholestasis(BRIC), associated with recurrent cholestatic attacks, to progressive FIC(PFIC). Patients often suffer from severe pruritus and eventually progressive cholestasis results in liver failure. Currently, first-line treatment includes ursodeoxycholic acid in patients with ABCB4 deficiency(PFIC3) and partial biliary diversion in patients with ATP8B1 or ABCB11 deficiency(PFIC1 and PFIC2). When treatment fails, liver transplantation is needed which is associated with complications like rejection, post-transplant hepatic steatosis and recurrence of disease. Therefore, the need for more and better therapies for this group of chronic diseases remains. Here, we discuss new symptomatic treatment options like total biliary diversion, pharmacological diversion of bile acids and hepatocyte transplantation. Furthermore, we focus on emerging mutation-targeted therapeutic strategies, providing an outlook for future personalized treatment for inherited cholestatic liver diseases.展开更多
This paper reports geochronological data of detrital zircons from the country rock and sedimentary xenoliths of the Cilincuo pluton（79±0.7 Ma） in the southern Yidun arc belt and the inherited zircons from the L...This paper reports geochronological data of detrital zircons from the country rock and sedimentary xenoliths of the Cilincuo pluton（79±0.7 Ma） in the southern Yidun arc belt and the inherited zircons from the Late Triassic granites in the eastern Yidun arc belt, eastern Tibet Plateau. Detrital zircons ages from the sedimentary xenoliths have four prominent peaks at 2.5–2.4 Ga, 1.9–1.8 Ga, 480–400 Ma, and 350–300 Ma, whereas those from the country rock exhibit another four prominent peaks at 1.9–1.8 Ga, 850–700 Ma, 480–400 Ma, and 300–250 Ma. Based on comparison with age data from previous studies, we suggest that the sedimentary xenoliths are from the Lanashan Formation and the major provenance of them is Qiangtang Block, Zhongza massif and South China Block, whereas the country rock belongs to the Lamaya Formation and the major provenance of them is similar to those of the neighbouring Songpan-Garzê terrane. In addition, the inherited zircons from the Late Triassic granites in the eastern Yidun arc belts have a prominent Neoproterozoic age population（900–700 Ma）, which suggests that there is an old basement with west Yangtze Craton affinity beneath the Triassic sediments. Combining with previous studies, we propose that the provenances of the formations vary from the Lanashan Formation to the Lamaya Formation which may indicate a record of the final closure of the Garzê-Litang Ocean.展开更多
Mutations in mitochondrial tRNA genes have been shown to be associated with maternally inherited syn-dromic and non-syndromic deafness. Among those, mutations such as tRNALeu(UUR) 3243A>G associated with syndromic ...Mutations in mitochondrial tRNA genes have been shown to be associated with maternally inherited syn-dromic and non-syndromic deafness. Among those, mutations such as tRNALeu(UUR) 3243A>G associated with syndromic deafness are often present in heteroplasmy, and the non-syndromic deafness-associated tRNA mu-tations including tRNASer(UCN) 7445A>G are often in homoplasmy or in high levels of heteroplasmy. These tRNA mutations are the primary factors underlying the development of hearing loss. However, other tRNA mutations such as tRNAThr 15927G>A and tRNASer(UCN) 7444G>A are insufficient to produce a deafness phe-notype, but always act in synergy with the primary mitochondrial DNA mutations, and can modulate their phenotypic manifestation. These tRNA mutations may alter the structure and function of the corresponding mitochondrial tRNAs and cause failures in tRNAs metabolism. Thereby, the impairment of mitochondrial protein synthesis and subsequent defects in respiration caused by these tRNA mutations, results in mitochon-drial dysfunctions and eventually leads to the development of hearing loss. Here, we summarized the deaf-ness-associated mitochondrial tRNA mutations and discussed the pathophysiology of these mitochondrial tRNA mutations, and we hope these data will provide a foundation for the early diagnosis, management, and treatment of maternally inherited deafness.展开更多
A small proportion of many cancers are due to inherited mutations in genes,which result in a high risk to the indi-vidual of developing specific cancers. There are several classes of genes that may be involved: tumour...A small proportion of many cancers are due to inherited mutations in genes,which result in a high risk to the indi-vidual of developing specific cancers. There are several classes of genes that may be involved: tumour suppressor genes,onco-genes,genes encoding proteins involved in DNA repair and cell cycle control,and genes involved in stimulating the angiogenic pathway. Alterations in susceptibility to cancer may also be due to variations in genes involved in carcinogen metabolism. This review discusses examples of some of these genes and the associated clinical conditions caused by the inheritance of mutations in such genes.展开更多
To assure the shareholders can look for their ＂legal＂ attorneys to renew the secret, once the secret sharing scheme is initialized, a secret sharing scheme with inherited characteristic is constructed. In this schem...To assure the shareholders can look for their ＂legal＂ attorneys to renew the secret, once the secret sharing scheme is initialized, a secret sharing scheme with inherited characteristic is constructed. In this scheme, each shareholder can produce a new share by his algorithm, which is equivalent to the primary one. Together with other shares, the primary secret can be renewed. Since this scheme is constructed not by replacing the primary share with a new share produced by the dealer in his primitive secret sharing scheme, so no matter how much shares the shareholder produces, these shares can not be gathered together to renew the secret in this scheme. Compared with the existing secret sharing schemes, this scheme provides more agility for the shareholders by investing each of them a function but not affect its security.展开更多
Hearing loss is one of the most common birth defects,with inherited genetic defects play an important role,contributing to about 60%of deafness occurring in infants.However,hearing impairment is genetically heterogene...Hearing loss is one of the most common birth defects,with inherited genetic defects play an important role,contributing to about 60%of deafness occurring in infants.However,hearing impairment is genetically heterogeneous,with both common and rare forms occurring due to mutations in estimated 500 genes.Due to the large number and presumably low mutation frequencies of those genes,it would be highly expensive and time-consuming to address this issue by conventional gene-by-gene Sanger sequencing.Next-generation sequencing is a revolutionary technology that allows the simultaneous screening of mutations in a large number of genes.It is cost effective compared to classical strategies of linkage analysis and direct sequencing when the number or size of genes is large,and thus has become a highly efficient strategy for identifying novel causative genes and mutations involved in heritable disease.In this review, we describe major NGS methodologies currently used for genetic disorders and highlight applications of these technologies in studies of molecular diagnosis and the discovery of genes implicated in non-syndromic hearing loss.展开更多
Liver transplantation(LT)remains the gold standard treatment for end stage liver disease in the pediatric population.For liver based metabolic disorders(LBMDs),the decision for LT is predicated on a different set of p...Liver transplantation(LT)remains the gold standard treatment for end stage liver disease in the pediatric population.For liver based metabolic disorders(LBMDs),the decision for LT is predicated on a different set of paradigms.With improved outcomes post-transplantation,LT is no longer merely life saving,but has the potential to also significantly improve quality of life.This review summarizes the clinical presentation,medical treatment and indications for LT for some of the common LBMDs.We also provide a practical update on the dilemmas and controversies surrounding the indications for transplantation,surgical considerations and prognosis and long terms outcomes for pediatric LT in LBMDs.Important progress has been made in understanding these diseases in recent years and with that we outline some of the new therapies that have emerged.展开更多
Inherited metabolic liver diseases arise from genetic mutations that lead to dis-ruptions in liver metabolic pathways and are predominantly observed in pedia-tric populations.The spectrum of genetic metabolic liver di...Inherited metabolic liver diseases arise from genetic mutations that lead to dis-ruptions in liver metabolic pathways and are predominantly observed in pedia-tric populations.The spectrum of genetic metabolic liver disorders is diverse,encompassing a range of conditions associated with aberrations in iron,copper,carbohydrate,lipid,protein,and amino acid metabolism.Historically,research in the domain of genetic metabolic liver diseases has predominantly concentrated on hepatic parenchymal cell alterations.Nevertheless,emerging studies suggest that inherited metabolic liver diseases exert significant influences on the immune microenvironment,both within the liver and systemically.This review endeavors to encapsulate the immunological features of genetic metabolic liver diseases,aiming to expand the horizons of researchers in this discipline,and to elucidate the underlying pathophysiological mechanisms pertinent to hereditary metabolic liver diseases and to propose innovative therapeutic approaches.展开更多
Inherited retinal diseases(IRD)are a leading cause of blindness in the working age population.The advances in ocular genetics,retinal imaging and molecular biology,have conspired to create the ideal environment for es...Inherited retinal diseases(IRD)are a leading cause of blindness in the working age population.The advances in ocular genetics,retinal imaging and molecular biology,have conspired to create the ideal environment for establishing treatments for IRD,with the first approved gene therapy and the commencement of multiple therapy trials.The scope of this review is to familiarize clinicians and scientists with the current landscape of retinal imaging in IRD.Herein we present in a comprehensive and concise manner the imaging findings of:(I)macular dystrophies(MD)[Stargardt disease(ABCA4),X-linked retinoschisis(RS1),Best disease(BEST1),pattern dystrophy(PRPH2),Sorsby fundus dystrophy(TIMP3),and autosomal dominant drusen(EFEMP1)],(II)cone and cone-rod dystrophies(GUCA1A,PRPH2,ABCA4 and RPGR),(III)cone dysfunction syndromes[achromatopsia(CNGA3,CNGB3,PDE6C,PDE6H,GNAT2,ATF6],blue-cone monochromatism(OPN1LW/OPN1MW array),oligocone trichromacy,bradyopsia(RGS9/R9AP)and Bornholm eye disease(OPN1LW/OPN1MW),(IV)Leber congenital amaurosis(GUCY2D,CEP290,CRB1,RDH12,RPE65,TULP1,AIPL1 and NMNAT1),(V)rod-cone dystrophies[retinitis pigmentosa,enhanced S-Cone syndrome(NR2E3),Bietti crystalline corneoretinal dystrophy(CYP4V2)],(VI)rod dysfunction syndromes(congenital stationary night blindness,fundus albipunctatus(RDH5),Oguchi disease(SAG,GRK1),and(VII)chorioretinal dystrophies[choroideremia(CHM),gyrate atrophy(OAT)].展开更多
Whether or not there is inherited basis for prostate cancer aggressiveness is not clear, but advances in DNA analysis should provide an answer to this question in the very near future.
●AIM:To describe the complex,overlapping phenotype of four Chinese patients with inherited retinal dystrophies(IRDs)who harbored two pathogenic genes simultaneously.●METHODS:This retrospective study included 4 patie...●AIM:To describe the complex,overlapping phenotype of four Chinese patients with inherited retinal dystrophies(IRDs)who harbored two pathogenic genes simultaneously.●METHODS:This retrospective study included 4 patients affected with IRDs.Medical and ophthalmic histories were obtained,and clinical examinations were performed.A specific Hereditary Eye Disease Enrichment Panel(HEDEP)based on exome capture technology was used for genetic screening.●RESULTS:Four patients were identified to harbor disease-causing variants in two different genes.Patient retinitis pigmentosa(RP)01-II:1 exhibited both classical ABCA4-induced Stargardt disease(STGD)1 and USH2 Aassociated RP,patient RP02-III:2 exhibited both classical ABCA4-induced STGD1 and CDH23-associated RP,patient RP03-II:1 exhibited both USH2 A-induced autosomal recessive retinitis pigmentosa(arRP)syndrome and SNRNP200-induced autosomal dominant retinitis pigmentosa(adRP),and patient RP04-II:2 exhibited USH2 Ainduced arRP syndrome and EYS-induced arRP at the same time.●CONCLUSION:Our study demonstrates that genotype–phenotype correlations and comprehensive genetic screening is crucial for diagnosing IRDs and helping family planning for patients suffering from the disease.展开更多
Objective To develop a few-shot learning(FSL) approach for classifying optical coherence tomography(OCT) images in patients with inherited retinal disorders(IRDs).Methods In this study, an FSL model based on a student...Objective To develop a few-shot learning(FSL) approach for classifying optical coherence tomography(OCT) images in patients with inherited retinal disorders(IRDs).Methods In this study, an FSL model based on a student–teacher learning framework was designed to classify images. 2,317 images from 189 participants were included. Of these, 1,126 images revealed IRDs, 533 were normal samples, and 658 were control samples.Results The FSL model achieved a total accuracy of 0.974–0.983, total sensitivity of 0.934–0.957, total specificity of 0.984–0.990, and total F1 score of 0.935–0.957, which were superior to the total accuracy of the baseline model of 0.943–0.954, total sensitivity of 0.866–0.886, total specificity of 0.962–0.971,and total F1 score of 0.859–0.885. The performance of most subclassifications also exhibited advantages. Moreover, the FSL model had a higher area under curves(AUC) of the receiver operating characteristic(ROC) curves in most subclassifications.Conclusion This study demonstrates the effective use of the FSL model for the classification of OCT images from patients with IRDs, normal, and control participants with a smaller volume of data. The general principle and similar network architectures can also be applied to other retinal diseases with a low prevalence.展开更多
Inherited peripheral neuropathies （or Charcot-Marie-Tooth disease, CMT） are a phenotypically and genetically heterogeneous group of disorders, which are currently untreatable. They are the most common inherited neur...Inherited peripheral neuropathies （or Charcot-Marie-Tooth disease, CMT） are a phenotypically and genetically heterogeneous group of disorders, which are currently untreatable. They are the most common inherited neuromuscular disorder, affecting around 1 in every 2,500 people （over 120,000 people in the US）. Based on clinical neurophysiological and histopathological features, inherited neuropathies can be divided into two major forms： demyelinating （type 1） and axonal （type 2） CMT （Saporta, 2014）.展开更多
Gene therapy has shown significant potential in treating various diseases,particularly inherited blood disorders such as hemophilia,sickle cell disease,and thalassemia.Advances in understanding the regulatory network ...Gene therapy has shown significant potential in treating various diseases,particularly inherited blood disorders such as hemophilia,sickle cell disease,and thalassemia.Advances in understanding the regulatory network of disease-associated genes have led to the identification of additional therapeutic targets for treatment,especially for β-hemoglobinopathies.Erythroid regulatory factor BCL11A offers the most promising therapeutic target for β-hemoglobinopathies,and reduction of its expression using the commercialized gene therapy product Casgevy has been approved for use in the UK and USA in 2023.Notably,the emergence of innovative gene editing technologies has further broadened the gene therapy landscape,presenting possibilities for treatment.Intensive studies indicate that base editing and prime editing,built upon CRISPR technology,enable precise single-base modification in hematopoietic stem cells for addressing inherited blood disorders ex vivo and in vivo.In this review,we present an overview of the current landscape of gene therapies,focusing on clinical research and gene therapy products for inherited blood disorders,evaluation of potential gene targets,and the gene editing tools employed in current gene therapy practices,which provides an insight for the establishment of safer and more effective gene therapy methods for a wider range of diseases in the future.展开更多
Fibroblast growth factor receptor 1(FGFR1)mutations are associated with congenital hypogonadotropic hypogonadism(CHH)through inheritance or spontaneous occurrence.We detected FGFR1 mutations in a Chinese cohort of 210...Fibroblast growth factor receptor 1(FGFR1)mutations are associated with congenital hypogonadotropic hypogonadism(CHH)through inheritance or spontaneous occurrence.We detected FGFR1 mutations in a Chinese cohort of 210 CHH patients at Peking Union Medical College Hospital(Beijing,China)using next-generation and Sanger sequencing.We assessed missense variant pathogenicity using six bioinformatics tools and compared clinical features and treatment outcomes between inherited and de novo mutation groups.Among 19 patients with FGFR1 mutations,three were recurrent,and 16 were novel variants.Sixteen of the novel mutations were likely pathogenic according to the American College of Medical Genetics and Genomics(ACMG)guidelines,with the prevalent P366L variant.The majority of FGFR1 mutations was inherited(57.9%),with frameshift mutations exclusive to the de novo mutation group.The inherited mutation group had a lower incidence of cryptorchidism,short stature,and skeletal deformities.In the inherited mutation group,luteinizing hormone(LH)levels were 0.5 IU l−1,follicle-stimulating hormone(FSH)levels were 1.0 IU l−1,and testosterone levels were 1.3 nmol l−1.In contrast,the de novo group had LH levels of 0.2 IU l−1,FSH levels of 0.5 IU l−1,and testosterone levels of 0.9 nmol l−1,indicating milder hypothalamus–pituitary–gonadal axis(HPGA)functional deficiency in the inherited group.The inherited mutation group showed a tendency toward higher spermatogenesis rates.In conclusion,this study underscores the predominance of inherited FGFR1 mutations and their association with milder HPGA dysfunction compared to de novo mutations,contributing to our understanding of the genetic and clinical aspects of FGFR1 mutations.展开更多
Inherited photoreceptor degeneration（IPD）：The human retina is a highly specialised tissue that enables the perception of light across a range of intensities and colours.It covers about65%of the inner surface of the...Inherited photoreceptor degeneration（IPD）：The human retina is a highly specialised tissue that enables the perception of light across a range of intensities and colours.It covers about65%of the inner surface of the eye and contains three layers of cells：the outer nuclear layer（ONL）containing the cell bodies and nuclei of the light-sensitive rod and cone photoreceptorswhose photopigment-containing outer segments form the photoreceptor layer; the inner nuclear layer （INL） containing bipolar, horizontal and amacrine cells; and the ganglion cell layer （GCL） from which the optic nerve arises. There are two layers of synaptic connections between these three layers： the photoreceptors synapse with second order neurons, mainly bi- polar cells, in the outer plexiform layer （OPL）, while in turn the bipolar cells form connections in the inner plexiform layer （IPL） with ganglion cells. The retinal pigment epithelium （RPE） lies directly behind the photoreceptor layer, is heavily pigmented to reduce scattering of light, and is essential for the nourishment, maintenance and metabolism of photoreceptors.展开更多
This editorial,comments on the article by Spartalis et al published in the recent issue of the World Journal of Cardiology.We here provide an outlook on potential ethical concerns related to the future application of ...This editorial,comments on the article by Spartalis et al published in the recent issue of the World Journal of Cardiology.We here provide an outlook on potential ethical concerns related to the future application of gene therapy in the field of inherited arrhythmias.As monogenic diseases with no or few therapeutic options available through standard care,inherited arrhythmias are ideal candidates to gene therapy in their treatment.Patients with inherited arrhythmias typically have a poor quality of life,especially young people engaged in agonistic sports.While genome editing for treatment of inherited arrhythmias still has theoretical application,advances in CRISPR/Cas9 technology now allows the generation of knock-in animal models of the disease.However,clinical translation is somehow expected soon and this make consistent discussing about ethical concerns related to gene editing in inherited arrhythmias.Genomic off-target activity is a known technical issue,but its relationship with ethnical and individual genetical diversity raises concerns about an equitable accessibility.Meanwhile,the costeffectiveness may further limit an equal distribution of gene therapies.The economic burden of gene therapies on healthcare systems is is increasingly recognized as a pressing concern.A growing body of studies are reporting uncertainty in payback periods with intuitive short-term effects for insurance-based healthcare systems,but potential concerns for universal healthcare systems in the long term as well.Altogether,those aspects strongly indicate a need of regulatory entities to manage those issues.展开更多
Genetic mutations in single genes lead to inherited forms of cardiac and muscle disease. Cardiomyopathy from genetic mutations may develop in early or later life and may be associated with heart failure or be asymptom...Genetic mutations in single genes lead to inherited forms of cardiac and muscle disease. Cardiomyopathy from genetic mutations may develop in early or later life and may be associated with heart failure or be asymptomatic.The range of clinical outcome with inherited cardiomyopathy within families where there is a single genetic defect is,in part,determined by other genetic variants.We hypothesized that the interaction of single gene mutations with common genetic variants was responsible for cardiac and muscle disease.In a mouse model, we used a whole genome approach to identify genes that cause more severe heart and muscle disease. We identified a genetic locus on chromosome 7 that was significantly associated with severe disease.We identified the causative gene as Ltbp4,a gene that encodes the latent TGFbeta binding protein.We found that increased TGFbeta signaling was seen in the severely affected heart and muscle compared to the mildly affected strain.We found that increased proteolytic cleavage of LTBP4 protein was associated with increased SMAD signaling.These data support a model where increased proteolytic cleavage of LTBP4 results in increased TGFbeta release and signaling.We also identified other genetic regions that influence the severity of cardiomyopathy in this model.A genetic region on chromosome 9 was specifically associated with increased cardiac fibrosis in cardiomyopathy.Identifying modifier genes helps explain pathways important for modulating heart and muscle disease and may point to pathways that can be used therapeutically.(Supported by NIH,the Muscular Dystrophy Association and the Doris Duke Charitable Foundation.)展开更多
文摘The bivariate interpolation in two dimensional space R2 is more complicated than that in one dimensional space R, because there is no Haar space of continuous functions in R2. Therefore, the bivariate interpolation has not a unique solution for a set of arbitrary distinct pairwise points. In this work, we suggest a type of basis which depends on the points such that the bivariate interpolation has the unique solution for any set of distinct pairwise points. In this case, the matrix of bivariate interpolation has the semi inherited factorization.
文摘Familial intrahepatic cholestasis(FIC) comprises a group of rare cholestatic liver diseases associated with canalicular transport defects resulting predominantly from mutations in ATP8B1, ABCB11 and ABCB4. Phe-notypes range from benign recurrent intrahepatic cholestasis(BRIC), associated with recurrent cholestatic attacks, to progressive FIC(PFIC). Patients often suffer from severe pruritus and eventually progressive cholestasis results in liver failure. Currently, first-line treatment includes ursodeoxycholic acid in patients with ABCB4 deficiency(PFIC3) and partial biliary diversion in patients with ATP8B1 or ABCB11 deficiency(PFIC1 and PFIC2). When treatment fails, liver transplantation is needed which is associated with complications like rejection, post-transplant hepatic steatosis and recurrence of disease. Therefore, the need for more and better therapies for this group of chronic diseases remains. Here, we discuss new symptomatic treatment options like total biliary diversion, pharmacological diversion of bile acids and hepatocyte transplantation. Furthermore, we focus on emerging mutation-targeted therapeutic strategies, providing an outlook for future personalized treatment for inherited cholestatic liver diseases.
基金supported by the China Geological Survey (No. 1212011121270)the China Postdoctoral Science Foundation Project (No. 2015M581921)
文摘This paper reports geochronological data of detrital zircons from the country rock and sedimentary xenoliths of the Cilincuo pluton（79±0.7 Ma） in the southern Yidun arc belt and the inherited zircons from the Late Triassic granites in the eastern Yidun arc belt, eastern Tibet Plateau. Detrital zircons ages from the sedimentary xenoliths have four prominent peaks at 2.5–2.4 Ga, 1.9–1.8 Ga, 480–400 Ma, and 350–300 Ma, whereas those from the country rock exhibit another four prominent peaks at 1.9–1.8 Ga, 850–700 Ma, 480–400 Ma, and 300–250 Ma. Based on comparison with age data from previous studies, we suggest that the sedimentary xenoliths are from the Lanashan Formation and the major provenance of them is Qiangtang Block, Zhongza massif and South China Block, whereas the country rock belongs to the Lamaya Formation and the major provenance of them is similar to those of the neighbouring Songpan-Garzê terrane. In addition, the inherited zircons from the Late Triassic granites in the eastern Yidun arc belts have a prominent Neoproterozoic age population（900–700 Ma）, which suggests that there is an old basement with west Yangtze Craton affinity beneath the Triassic sediments. Combining with previous studies, we propose that the provenances of the formations vary from the Lanashan Formation to the Lamaya Formation which may indicate a record of the final closure of the Garzê-Litang Ocean.
基金supported by grants from The National Natural Science Foundation of China(81070794 and 31100903)The Natural Science Foundation of Zhejiang Province(Y2110399)The China Postdoctoral Science Foundation(2013M531472)
文摘Mutations in mitochondrial tRNA genes have been shown to be associated with maternally inherited syn-dromic and non-syndromic deafness. Among those, mutations such as tRNALeu(UUR) 3243A>G associated with syndromic deafness are often present in heteroplasmy, and the non-syndromic deafness-associated tRNA mu-tations including tRNASer(UCN) 7445A>G are often in homoplasmy or in high levels of heteroplasmy. These tRNA mutations are the primary factors underlying the development of hearing loss. However, other tRNA mutations such as tRNAThr 15927G>A and tRNASer(UCN) 7444G>A are insufficient to produce a deafness phe-notype, but always act in synergy with the primary mitochondrial DNA mutations, and can modulate their phenotypic manifestation. These tRNA mutations may alter the structure and function of the corresponding mitochondrial tRNAs and cause failures in tRNAs metabolism. Thereby, the impairment of mitochondrial protein synthesis and subsequent defects in respiration caused by these tRNA mutations, results in mitochon-drial dysfunctions and eventually leads to the development of hearing loss. Here, we summarized the deaf-ness-associated mitochondrial tRNA mutations and discussed the pathophysiology of these mitochondrial tRNA mutations, and we hope these data will provide a foundation for the early diagnosis, management, and treatment of maternally inherited deafness.
文摘A small proportion of many cancers are due to inherited mutations in genes,which result in a high risk to the indi-vidual of developing specific cancers. There are several classes of genes that may be involved: tumour suppressor genes,onco-genes,genes encoding proteins involved in DNA repair and cell cycle control,and genes involved in stimulating the angiogenic pathway. Alterations in susceptibility to cancer may also be due to variations in genes involved in carcinogen metabolism. This review discusses examples of some of these genes and the associated clinical conditions caused by the inheritance of mutations in such genes.
基金This project was supported by Young Teacher Foundation of North China Elec. Power Univ.(200521001)
文摘To assure the shareholders can look for their ＂legal＂ attorneys to renew the secret, once the secret sharing scheme is initialized, a secret sharing scheme with inherited characteristic is constructed. In this scheme, each shareholder can produce a new share by his algorithm, which is equivalent to the primary one. Together with other shares, the primary secret can be renewed. Since this scheme is constructed not by replacing the primary share with a new share produced by the dealer in his primitive secret sharing scheme, so no matter how much shares the shareholder produces, these shares can not be gathered together to renew the secret in this scheme. Compared with the existing secret sharing schemes, this scheme provides more agility for the shareholders by investing each of them a function but not affect its security.
基金supported by grants from the Project of the National Natural Science Foundation of China(Grant Nos.30801285,81230020,81200751,81070792,81000415, 81360159)grants from China Postdoctoral Science Foundation(No.2012M,2013T52187860947)a grant from Minister of Science and Technology of China(2012BAI09B02)
文摘Hearing loss is one of the most common birth defects,with inherited genetic defects play an important role,contributing to about 60%of deafness occurring in infants.However,hearing impairment is genetically heterogeneous,with both common and rare forms occurring due to mutations in estimated 500 genes.Due to the large number and presumably low mutation frequencies of those genes,it would be highly expensive and time-consuming to address this issue by conventional gene-by-gene Sanger sequencing.Next-generation sequencing is a revolutionary technology that allows the simultaneous screening of mutations in a large number of genes.It is cost effective compared to classical strategies of linkage analysis and direct sequencing when the number or size of genes is large,and thus has become a highly efficient strategy for identifying novel causative genes and mutations involved in heritable disease.In this review, we describe major NGS methodologies currently used for genetic disorders and highlight applications of these technologies in studies of molecular diagnosis and the discovery of genes implicated in non-syndromic hearing loss.
文摘Liver transplantation(LT)remains the gold standard treatment for end stage liver disease in the pediatric population.For liver based metabolic disorders(LBMDs),the decision for LT is predicated on a different set of paradigms.With improved outcomes post-transplantation,LT is no longer merely life saving,but has the potential to also significantly improve quality of life.This review summarizes the clinical presentation,medical treatment and indications for LT for some of the common LBMDs.We also provide a practical update on the dilemmas and controversies surrounding the indications for transplantation,surgical considerations and prognosis and long terms outcomes for pediatric LT in LBMDs.Important progress has been made in understanding these diseases in recent years and with that we outline some of the new therapies that have emerged.
基金Supported by Shanghai Science and Technology Development Foundation(Outstanding Academic Leader),No.23XD1423100National Natural Science Foundation,No.82241221 and No.92059205。
文摘Inherited metabolic liver diseases arise from genetic mutations that lead to dis-ruptions in liver metabolic pathways and are predominantly observed in pedia-tric populations.The spectrum of genetic metabolic liver disorders is diverse,encompassing a range of conditions associated with aberrations in iron,copper,carbohydrate,lipid,protein,and amino acid metabolism.Historically,research in the domain of genetic metabolic liver diseases has predominantly concentrated on hepatic parenchymal cell alterations.Nevertheless,emerging studies suggest that inherited metabolic liver diseases exert significant influences on the immune microenvironment,both within the liver and systemically.This review endeavors to encapsulate the immunological features of genetic metabolic liver diseases,aiming to expand the horizons of researchers in this discipline,and to elucidate the underlying pathophysiological mechanisms pertinent to hereditary metabolic liver diseases and to propose innovative therapeutic approaches.
基金Supported by grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology,Macular Society(UK),Fight for Sight(UK),Onassis Foundation,Leventis Foundation,The Wellcome Trust(099173/Z/12/Z)Moorfields Eye Hospital Special Trustees,Moorfields Eye Charity,Retina UK,and the Foundation Fighting Blindness(USA).
文摘Inherited retinal diseases(IRD)are a leading cause of blindness in the working age population.The advances in ocular genetics,retinal imaging and molecular biology,have conspired to create the ideal environment for establishing treatments for IRD,with the first approved gene therapy and the commencement of multiple therapy trials.The scope of this review is to familiarize clinicians and scientists with the current landscape of retinal imaging in IRD.Herein we present in a comprehensive and concise manner the imaging findings of:(I)macular dystrophies(MD)[Stargardt disease(ABCA4),X-linked retinoschisis(RS1),Best disease(BEST1),pattern dystrophy(PRPH2),Sorsby fundus dystrophy(TIMP3),and autosomal dominant drusen(EFEMP1)],(II)cone and cone-rod dystrophies(GUCA1A,PRPH2,ABCA4 and RPGR),(III)cone dysfunction syndromes[achromatopsia(CNGA3,CNGB3,PDE6C,PDE6H,GNAT2,ATF6],blue-cone monochromatism(OPN1LW/OPN1MW array),oligocone trichromacy,bradyopsia(RGS9/R9AP)and Bornholm eye disease(OPN1LW/OPN1MW),(IV)Leber congenital amaurosis(GUCY2D,CEP290,CRB1,RDH12,RPE65,TULP1,AIPL1 and NMNAT1),(V)rod-cone dystrophies[retinitis pigmentosa,enhanced S-Cone syndrome(NR2E3),Bietti crystalline corneoretinal dystrophy(CYP4V2)],(VI)rod dysfunction syndromes(congenital stationary night blindness,fundus albipunctatus(RDH5),Oguchi disease(SAG,GRK1),and(VII)chorioretinal dystrophies[choroideremia(CHM),gyrate atrophy(OAT)].
文摘Whether or not there is inherited basis for prostate cancer aggressiveness is not clear, but advances in DNA analysis should provide an answer to this question in the very near future.
基金Supported by the National Natural Science Foundation of China(No.81770966,No.81470666,No.81271046)a Joint Program of Beijing Municipal NaturalScience Foundation(Category B)Beijing Educational committee(No.KZ201510025025).
文摘●AIM:To describe the complex,overlapping phenotype of four Chinese patients with inherited retinal dystrophies(IRDs)who harbored two pathogenic genes simultaneously.●METHODS:This retrospective study included 4 patients affected with IRDs.Medical and ophthalmic histories were obtained,and clinical examinations were performed.A specific Hereditary Eye Disease Enrichment Panel(HEDEP)based on exome capture technology was used for genetic screening.●RESULTS:Four patients were identified to harbor disease-causing variants in two different genes.Patient retinitis pigmentosa(RP)01-II:1 exhibited both classical ABCA4-induced Stargardt disease(STGD)1 and USH2 Aassociated RP,patient RP02-III:2 exhibited both classical ABCA4-induced STGD1 and CDH23-associated RP,patient RP03-II:1 exhibited both USH2 A-induced autosomal recessive retinitis pigmentosa(arRP)syndrome and SNRNP200-induced autosomal dominant retinitis pigmentosa(adRP),and patient RP04-II:2 exhibited USH2 Ainduced arRP syndrome and EYS-induced arRP at the same time.●CONCLUSION:Our study demonstrates that genotype–phenotype correlations and comprehensive genetic screening is crucial for diagnosing IRDs and helping family planning for patients suffering from the disease.
基金supported by National Natural Science Foundation of China [No.82171073]。
文摘Objective To develop a few-shot learning(FSL) approach for classifying optical coherence tomography(OCT) images in patients with inherited retinal disorders(IRDs).Methods In this study, an FSL model based on a student–teacher learning framework was designed to classify images. 2,317 images from 189 participants were included. Of these, 1,126 images revealed IRDs, 533 were normal samples, and 658 were control samples.Results The FSL model achieved a total accuracy of 0.974–0.983, total sensitivity of 0.934–0.957, total specificity of 0.984–0.990, and total F1 score of 0.935–0.957, which were superior to the total accuracy of the baseline model of 0.943–0.954, total sensitivity of 0.866–0.886, total specificity of 0.962–0.971,and total F1 score of 0.859–0.885. The performance of most subclassifications also exhibited advantages. Moreover, the FSL model had a higher area under curves(AUC) of the receiver operating characteristic(ROC) curves in most subclassifications.Conclusion This study demonstrates the effective use of the FSL model for the classification of OCT images from patients with IRDs, normal, and control participants with a smaller volume of data. The general principle and similar network architectures can also be applied to other retinal diseases with a low prevalence.
文摘Inherited peripheral neuropathies （or Charcot-Marie-Tooth disease, CMT） are a phenotypically and genetically heterogeneous group of disorders, which are currently untreatable. They are the most common inherited neuromuscular disorder, affecting around 1 in every 2,500 people （over 120,000 people in the US）. Based on clinical neurophysiological and histopathological features, inherited neuropathies can be divided into two major forms： demyelinating （type 1） and axonal （type 2） CMT （Saporta, 2014）.
基金supported by Research Fund of Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital(30420230006)the National Natural Science Foundation of China(Nos.82300142)Sichuan Science and Technology Program(2022ZYD0131)。
文摘Gene therapy has shown significant potential in treating various diseases,particularly inherited blood disorders such as hemophilia,sickle cell disease,and thalassemia.Advances in understanding the regulatory network of disease-associated genes have led to the identification of additional therapeutic targets for treatment,especially for β-hemoglobinopathies.Erythroid regulatory factor BCL11A offers the most promising therapeutic target for β-hemoglobinopathies,and reduction of its expression using the commercialized gene therapy product Casgevy has been approved for use in the UK and USA in 2023.Notably,the emergence of innovative gene editing technologies has further broadened the gene therapy landscape,presenting possibilities for treatment.Intensive studies indicate that base editing and prime editing,built upon CRISPR technology,enable precise single-base modification in hematopoietic stem cells for addressing inherited blood disorders ex vivo and in vivo.In this review,we present an overview of the current landscape of gene therapies,focusing on clinical research and gene therapy products for inherited blood disorders,evaluation of potential gene targets,and the gene editing tools employed in current gene therapy practices,which provides an insight for the establishment of safer and more effective gene therapy methods for a wider range of diseases in the future.
基金Natural Science Foundation of Beijing(grant No.7212080)National Natural Science Foundation of China(grant No.81971375)+2 种基金National High Level Hospital Clinical Research Funding(2022-PUMCH-D-002)CAMS Innovation Fund for Medical Sciences(CIFMS 2021-I2M-1-003)National High Level Hospital Clinical Research Funding(2022-PUMCH-C-028).
文摘Fibroblast growth factor receptor 1(FGFR1)mutations are associated with congenital hypogonadotropic hypogonadism(CHH)through inheritance or spontaneous occurrence.We detected FGFR1 mutations in a Chinese cohort of 210 CHH patients at Peking Union Medical College Hospital(Beijing,China)using next-generation and Sanger sequencing.We assessed missense variant pathogenicity using six bioinformatics tools and compared clinical features and treatment outcomes between inherited and de novo mutation groups.Among 19 patients with FGFR1 mutations,three were recurrent,and 16 were novel variants.Sixteen of the novel mutations were likely pathogenic according to the American College of Medical Genetics and Genomics(ACMG)guidelines,with the prevalent P366L variant.The majority of FGFR1 mutations was inherited(57.9%),with frameshift mutations exclusive to the de novo mutation group.The inherited mutation group had a lower incidence of cryptorchidism,short stature,and skeletal deformities.In the inherited mutation group,luteinizing hormone(LH)levels were 0.5 IU l−1,follicle-stimulating hormone(FSH)levels were 1.0 IU l−1,and testosterone levels were 1.3 nmol l−1.In contrast,the de novo group had LH levels of 0.2 IU l−1,FSH levels of 0.5 IU l−1,and testosterone levels of 0.9 nmol l−1,indicating milder hypothalamus–pituitary–gonadal axis(HPGA)functional deficiency in the inherited group.The inherited mutation group showed a tendency toward higher spermatogenesis rates.In conclusion,this study underscores the predominance of inherited FGFR1 mutations and their association with milder HPGA dysfunction compared to de novo mutations,contributing to our understanding of the genetic and clinical aspects of FGFR1 mutations.
基金Work in Dr.Shu’s lab was supported by the Rosetrees Trust(No.M160 and M160-F1)the Fight for Sight,the Glasgow Children’s Hospital Charity(No.YRSS/PSG/2014)the Visual Research Trust(No.VR2014)
文摘Inherited photoreceptor degeneration（IPD）：The human retina is a highly specialised tissue that enables the perception of light across a range of intensities and colours.It covers about65%of the inner surface of the eye and contains three layers of cells：the outer nuclear layer（ONL）containing the cell bodies and nuclei of the light-sensitive rod and cone photoreceptorswhose photopigment-containing outer segments form the photoreceptor layer; the inner nuclear layer （INL） containing bipolar, horizontal and amacrine cells; and the ganglion cell layer （GCL） from which the optic nerve arises. There are two layers of synaptic connections between these three layers： the photoreceptors synapse with second order neurons, mainly bi- polar cells, in the outer plexiform layer （OPL）, while in turn the bipolar cells form connections in the inner plexiform layer （IPL） with ganglion cells. The retinal pigment epithelium （RPE） lies directly behind the photoreceptor layer, is heavily pigmented to reduce scattering of light, and is essential for the nourishment, maintenance and metabolism of photoreceptors.
文摘This editorial,comments on the article by Spartalis et al published in the recent issue of the World Journal of Cardiology.We here provide an outlook on potential ethical concerns related to the future application of gene therapy in the field of inherited arrhythmias.As monogenic diseases with no or few therapeutic options available through standard care,inherited arrhythmias are ideal candidates to gene therapy in their treatment.Patients with inherited arrhythmias typically have a poor quality of life,especially young people engaged in agonistic sports.While genome editing for treatment of inherited arrhythmias still has theoretical application,advances in CRISPR/Cas9 technology now allows the generation of knock-in animal models of the disease.However,clinical translation is somehow expected soon and this make consistent discussing about ethical concerns related to gene editing in inherited arrhythmias.Genomic off-target activity is a known technical issue,but its relationship with ethnical and individual genetical diversity raises concerns about an equitable accessibility.Meanwhile,the costeffectiveness may further limit an equal distribution of gene therapies.The economic burden of gene therapies on healthcare systems is is increasingly recognized as a pressing concern.A growing body of studies are reporting uncertainty in payback periods with intuitive short-term effects for insurance-based healthcare systems,but potential concerns for universal healthcare systems in the long term as well.Altogether,those aspects strongly indicate a need of regulatory entities to manage those issues.
文摘Genetic mutations in single genes lead to inherited forms of cardiac and muscle disease. Cardiomyopathy from genetic mutations may develop in early or later life and may be associated with heart failure or be asymptomatic.The range of clinical outcome with inherited cardiomyopathy within families where there is a single genetic defect is,in part,determined by other genetic variants.We hypothesized that the interaction of single gene mutations with common genetic variants was responsible for cardiac and muscle disease.In a mouse model, we used a whole genome approach to identify genes that cause more severe heart and muscle disease. We identified a genetic locus on chromosome 7 that was significantly associated with severe disease.We identified the causative gene as Ltbp4,a gene that encodes the latent TGFbeta binding protein.We found that increased TGFbeta signaling was seen in the severely affected heart and muscle compared to the mildly affected strain.We found that increased proteolytic cleavage of LTBP4 protein was associated with increased SMAD signaling.These data support a model where increased proteolytic cleavage of LTBP4 results in increased TGFbeta release and signaling.We also identified other genetic regions that influence the severity of cardiomyopathy in this model.A genetic region on chromosome 9 was specifically associated with increased cardiac fibrosis in cardiomyopathy.Identifying modifier genes helps explain pathways important for modulating heart and muscle disease and may point to pathways that can be used therapeutically.(Supported by NIH,the Muscular Dystrophy Association and the Doris Duke Charitable Foundation.)
