Genetic factors may be learnt from families with gene mutations that render nerve-injury sus- ceptibility even to ordinary physical activities. A typical example is hereditary neuropathy with liability to pressure pal...Genetic factors may be learnt from families with gene mutations that render nerve-injury sus- ceptibility even to ordinary physical activities. A typical example is hereditary neuropathy with liability to pressure palsies （HNPP）. HNPP is caused by a heterozygous deletion of PMP22 gene. PMP22 deficiency disrupts myelin junctions （such as tight junction and adherens junctions）, leading to abnormally increased myelin permeability that explains the nerve susceptibility to injury. This finding should motivate investigators to identify additional genetic factors contribut- ing to nerve vulnerability of injury.展开更多
AIM: To develop a risk model for Crohn’s disease (CD) based on homogeneous population.METHODS: In our study were included 160 CD patients and 209 healthy individuals from Slovenia. The association study wa...AIM: To develop a risk model for Crohn’s disease (CD) based on homogeneous population.METHODS: In our study were included 160 CD patients and 209 healthy individuals from Slovenia. The association study was performed for 112 single nucleotide polymorphisms (SNPs). We generated genetic risk scores (GRS) based on the number of risk alleles using weighted additive model. Discriminatory accuracy was measured by area under ROC curve (AUC). For risk evaluation, we divided individuals according to positive and negative likelihood ratios (LR) of a test, with LR > 5 for high risk group and LR < 0.20 for low risk group.RESULTS: The highest accuracy, AUC of 0.78 was achieved with GRS combining 33 SNPs with optimal sensitivity and specificity of 75.0% and 72.7%, respectively. Individuals with the highest risk (GRS > 5.54) showed significantly increased odds of developing CD (OR = 26.65, 95%CI: 11.25-63.15) compared to the individuals with the lowest risk (GRS < 4.57) which is a considerably greater risk captured than in one SNP with the highest effect size (OR = 3.24). When more than 33 SNPs were included in GRS, discriminatory ability was not improved significantly; AUC of all 74 SNPs was 0.76.CONCLUSION: The authors proved the possibility of building accurate genetic risk score based on 33 risk variants on Slovenian CD patients which may serve as a screening tool in the targeted population.展开更多
Background: The inadequacy in the completeness of the Laboratory Request Form (LRF) has been reported as one of the major sources of errors during the pre-analytical step of laboratory analysis. To prevent the occurre...Background: The inadequacy in the completeness of the Laboratory Request Form (LRF) has been reported as one of the major sources of errors during the pre-analytical step of laboratory analysis. To prevent the occurrence of such errors, this study aimed at assessing the level of completeness of LRFs. Methods: A retrospective analysis of laboratory request forms was conducted at the Clinical Biology Laboratory of the Kinshasa University Clinic, DR Congo, between November 2021 to May 2022. The LRFs were evaluated according to the completeness of all sections including administrative data of the patient, data of physician who ordered the test, relevant patient’s clinical data and data of the biological sample. Results: From a total of 2842 LRFs evaluated, none was fully completed with all required information. Particularly, patient’s clinical data including the medical history, provisional diagnosis and current treatment, were the most absent in 99% LRFs. However, two sections related to patient’s ID and prescribed test were informed in 100% LRFs. Conclusion: The results of this preanalytical audit can serve as an improvement opportunity focused on strengthening awareness about complete filling of LRF.展开更多
Recurrent genomic imbalances at 16p 11.2 are genetic risk factors of variable penetrance for developmental delay and autism.Recently, 16pl 1.2（chr16：29.5 Mb-30.1 Mb） deletion has also been detected in individuals w...Recurrent genomic imbalances at 16p 11.2 are genetic risk factors of variable penetrance for developmental delay and autism.Recently, 16pl 1.2（chr16：29.5 Mb-30.1 Mb） deletion has also been detected in individuals with early-onset severe obesity.The penetrance of 16p11.2 deletion as a genetic risk factor for obesity is unknown.We evaluated the growth and body mass characteristics of 28 individuals with 16p11.2 （chr16：29.5 Mb-30.1 Mb） deletion originally ascertained for their developmental disorders by reviewing their medical records.We found that nine individuals could be classified as obese and six as overweight.These individuals generally had early feeding and growth difficulties,and started to gain excessive weight around 5-6 years of age.Thirteen out of the 18 deletion carriers aged 5 years and older（72%） were overweight or obese,whereas only two of 10 deletion carriers（20%） younger than five were overweight or obese.Males exhibited more severe obesity than females.Thus,the obesity phenotype of 16p11.2 deletion carriers is of juvenile onset,exhibited an age- and gender-dependent penetrance. 16p11.2 deletion appears to predispose individuals to juvenile onset obesity and in this case are similar to the well-described Prader-Willi syndrome（PWS）.Early detection of this deletion will provide opportunity to prevent obesity.展开更多
Objective: Pelvic organ prolapse is an emerging public health problem affecting adult women of all ages with a negative impact on social, physical well-being, and psychological. Its presents several challenges in coun...Objective: Pelvic organ prolapse is an emerging public health problem affecting adult women of all ages with a negative impact on social, physical well-being, and psychological. Its presents several challenges in countries with low resources. This literature review aims to examine POP in its epidemiological aspects, risk factors, and staging by taking up the challenges associated with low-resource settings and identifying some avenues for future research. Methods: We searched the PubMed, Google Scholar, and Scopus databases. The other studies were identified by checking the secondary references in the original citation. We have collected studies on adult women published in English for the last 30 years. In total, 71 articles were read. We excluded studies from all newspaper articles, Studies presenting co-morbidities (fistulas, cervical cancer, pregnancy), those evaluating treatment, letters, comments, case reports, practice guidelines, news, historical articles, legal cases, published erratum, and congresses. Results: 16 studies examining the epidemiology have been identified with 11 in countries defined by the World Bank as limited or intermediate resources. 18 on risk factors whose 10 in countries with limited or intermediate resources, 10 on staging and 27 on physiopathology. Conclusion: POP affects the young more in low-resource settings. Its prevalence remains underestimated for several reasons. Several risk factors found are the same as those of women in countries with a high standard of living. However, there are some specific risk factors for these resource-limited settings.展开更多
AIM:To study the associations between lysyl oxidaselike 1(LOXL1)polymorphisms and primary open angle glaucoma(POAG)remain inconsistent.In this study,we have performed a meta-analysis to investigate the association of ...AIM:To study the associations between lysyl oxidaselike 1(LOXL1)polymorphisms and primary open angle glaucoma(POAG)remain inconsistent.In this study,we have performed a meta-analysis to investigate the association of LOXL1 polymorphisms with POAG risk.METHODS:Published literature from PubMed and other databases were retrieved.All studies evaluating the association between LOXL1 polymorphisms(rs2165241,rs1048661,rs3825942)and POAG risk were included.Pooled odds ratio(OR)and 95%confidence interval(CI)were calculated using random-or fixed-effects model.RESULTS:Twelve studies were identified as eligible articles,with thirteen(2098 cases and 16 473 controls),thirteen(1795 cases and 2916 controls)and sixteen population cohorts(2456 cases and 2846 controls)for the association of rs2165241,rs1048661 and rs3825942with POAG risk respectively.Overall analyses showed noassociation between each LOXL1 polymorphism and POAG risk,and the negative associations were remained when the subjects were stratified as Caucasian and Asian.The heterozygote of rs2165241 was associated with reduced POAG risk in hospital-based populations(TC vs CC:OR,0.79,95%CI:0.63-0.99),and rs1048661was associated with increased POAG risk in hospitalbased populations in a dominant model(TT vs CC+CT:OR,1.23,95%CI:1.01-1.50);however,these associations were not found in population-based subjects.CONCLUSION:This meta-analysis suggests that LOXL1 polymorphisms are not associated with POAG risk.Given the limited sample size,the associations of LOXL1 polymorphisms with POAG risk in hospital-based populations await further investigation.展开更多
wide association studies(GWAS)in recent years.Since the identification of variants in the complement factor H gene on the risk of age-related macular degeneration,GWAS have become ubiquitous in genetic studies and hav...wide association studies(GWAS)in recent years.Since the identification of variants in the complement factor H gene on the risk of age-related macular degeneration,GWAS have become ubiquitous in genetic studies and have led to the identification of genetic variants that are associated with a variety of complex human diseases and traits.These discoveries have changed our understanding of the biological architecture of common,complex diseases and have also provided new hypotheses to test.New tools,such as next-generation sequencing,will be an important part of the future of genetics research;however,GWAS studies will continue to play an important role in disease gene discovery.Many traits have yet to be explored by GWAS,especially in minority populations,and large collaborative studies are currently being conducted to maximize the return from existing GWAS data.In addition,GWAS technology continues to improve,increasing genomic coverage for major global populations and decreasing the cost of experiments.Although much of the variance attributable to genetic factors for many important traits is still unexplained,GWAS technology has been instrumental in mapping over a thousand genes to hundreds of traits.More discoveries are made each month and the scale,quality and quantity of current work has a steady trend upward.We briefly review the current key trends in GWAS,which can be summarized with three goals:increase power,increase collaborations and increase populations.展开更多
Sickle cell anemia (SCA) is an autosomal-recessive hemoglobinopathy with a highly variable phenotype. Multiple clinical complications are characteristic of SCA including inflammatory and oxidant damage to both small a...Sickle cell anemia (SCA) is an autosomal-recessive hemoglobinopathy with a highly variable phenotype. Multiple clinical complications are characteristic of SCA including inflammatory and oxidant damage to both small and large blood vessels, hemolysis, vasoocclusion, and premature mortality. The overall severity of SCA is affected by multiple genetic modifier loci, including ARFGEF2, a gene known to modify TNF-α receptor release from human endothelial cells. In this report, we examine the effect of siRNA mediated knockdown of ARFGEF2 inhuman pulmonary artery endothelial cells and report that TNF-α induced expression of ICAM1 and VCAM1, both important mediators of endo-thelial-leukocyte adhesion, is significantly enhanced after ARFGEF2 knockdown. Levels of ICAM-1 protein are also increased in TNF-α treated endothelial cells after ARFGEF2 knockdown;the increased ICAM-1 appears to be localized in the cytoplasm. IL-1β stimulation of endothelial cells without ARFGEF2 produced enhanced ICAM1 expression only. Additionally, ARFGEF2 knockdown distinctly altered endothelial cell morphology. Large-vessel pathology in SCA is believed to begin with endothelial activation by inflammatory cytokines and adhesion of sickle erythrocytes and leukocytes, leading to a progressive vasculopathy characterized by smooth muscle cell migration and proliferation. Understanding how variability in the function of ARFGEF2 alters the response of pulmonary vasculature to TNF-α might suggest new targets for SCA treatment.展开更多
Objective: Charcot-Marie-Tooth (CMT) neuropathy with visual impairment due to optic atrophy has been designated as hereditary motor and sensory neuropathy type VI (HMSN VI). Reports of affected families have indicated...Objective: Charcot-Marie-Tooth (CMT) neuropathy with visual impairment due to optic atrophy has been designated as hereditary motor and sensory neuropathy type VI (HMSN VI). Reports of affected families have indicated autosomal dominant and recessive forms,but the genetic cause of this disease has remained elusive. Methods:Here,we describe six HMSN VI families with a subacute onset of optic atrophy and subsequent slow recovery of visual acuity in 60% of the patients. Detailed clinical and genetic studies were performed. Results: In each pedigree,we identified a unique mutation in the gene mitofusin 2 (MFN2). In three families,the MFN2 mutation occurred de novo; in two families the mutation was subsequently transmitted from father to son indicating autosomal dominant inheritance. Interpretation: MFN2 is a mitochondrial membrane protein that was recently reported to cause axonal CMT type 2A. It is intriguing that MFN2 shows functional overlap with optic atrophy 1 (OPA1),the protein underlying the most common form of autosomal dominant optic atrophy,and mitochondrial encoded oxidative phosphorylation components as seen in Leber’ s hereditary optic atrophy. We conclude that autosomal dominant HMSN VI is caused by mutations in MFN2,emphasizing the important role of mitochondrial function for both optic atrophies and peripheral neuropathies.展开更多
The purpose of this study was to perform morphological and molecular analyses of articular cartilage from a 14-year-old boy with unusual cartilage lesions, patella alta and trochlea dysplasia in both knee joints and c...The purpose of this study was to perform morphological and molecular analyses of articular cartilage from a 14-year-old boy with unusual cartilage lesions, patella alta and trochlea dysplasia in both knee joints and clinically examine two family members (sister, mother), also affected in their knee joints. Biopsies from the boy’s patella were used for: histological examination, Transmission Electron Microscopy (TEM) and DNA sequencing of the COL2A1 gene including Multiplex Ligation-dependent Probe Amplification (MLPA), for detection of DNA deletions and duplications. Clinical and radiological examination showed patella alta and trochlea dysplasia for the brother (type D), sister (type A) and mother (type A) with Insall-Salvati ratios of 1.50, 1.46 and 1.3. Light Microscopy (LM) of biopsies from the patient showed rhomboid chondrocytes in lacuna with deposition of protein aggregates in the ECM. TEM revealed abnormal type II collagen fibrils in aggregates and chondrocytes with abnormal matrix accumulation in rough Endoplasmic Reticulum (rER). Immunostaining showed that type II collagen was deposited intracellularly and in protein aggregates, together with type I collagen, indicating alterations in chondrocyte function and turnover of these molecules. DNA sequencing of 54 exons including extended DNA analysis with MLPA was non-conclusive. Conclusions: We suggest that patella alta and trochlea dysplasia for this patient is associated with collagen accumulation in chondrocytes, abnormal type II collagen heterofibrils in the ECM, cell death and cartilage with subnormal strength and increased risk of premature patellofemoral arthritis. A family with these disorders suggests that phenotype might be transmitted as an autosomal dominant trait.展开更多
Human genetic variants can influence the severity of symptoms infected with SARS-COV-2.Several genome-wide asso-ciation studies have identified human genomic risk single nucleotide polymorphisms(SNPs)associated with c...Human genetic variants can influence the severity of symptoms infected with SARS-COV-2.Several genome-wide asso-ciation studies have identified human genomic risk single nucleotide polymorphisms(SNPs)associated with coronavirus disease 2019(COVID-19)severity.However,the causal tissues or cell types underlying COVID-19 severity are uncertain.In addition,candidate genes associated with these risk SNPs were investigated based on genomic proximity instead of their functional cellular contexts.Here,we compiled regulatory networks of 77 human contexts and revealed those risk SNPs’enriched cellular contexts and associated risk SNPs with transcription factors,regulatory elements,and target genes.Twenty-one human contexts were identified and grouped into two categories:immune cells and epithelium cells.We further aggregated the regulatory networks of immune cells and epithelium cells.These two aggregated regulatory networks were investigated to reveal their association with risk SNPs’regulation.Two genomic clusters,the chemokine receptors cluster and the oligoadenylate synthetase(OAS)cluster,showed the strongest association with COVID-19 severity,and they had different regulatory programs in immune and epithelium contexts.Our findings were supported by analysis of both SNP array and whole genome sequencing-based genome wide association study(GWAS)summary statistics.展开更多
Background:There are several clinical reports about the co-occurrence of autosomal dominant polycystic kidney disease(ADPKD)and connective tissue disorders.A simultaneous occurrence of osteogenesis imperfecta(OI)type ...Background:There are several clinical reports about the co-occurrence of autosomal dominant polycystic kidney disease(ADPKD)and connective tissue disorders.A simultaneous occurrence of osteogenesis imperfecta(OI)type I and ADPKD has not been observed so far.Methods:This report presents the first patient with OI type I and ADPKD.Results:Mutational analysis of PKD1 and COL1A1 in the index patient revealed a heterozygous mutation in each of the two genes.Mutational analysis of the parents indicated the mother as a carrier of the PKD1 mutation and the father as a carrier of the COL1A1 mutation.The simultaneous occurrence of both disorders has an estimated frequency of 3.5:100000000.Conclusion:In singular cases,ADPKD can occur in combination with other rare disorders,e.g.connective tissue disorders.展开更多
Formation of claudin-10 based tight junctions(TJs)is paramount to paracellular Na+transport in multiple epithelia.Sequence variants in CLDN10 have been linked to HELIX syndrome,a salt-losing tubulopathy with altered h...Formation of claudin-10 based tight junctions(TJs)is paramount to paracellular Na+transport in multiple epithelia.Sequence variants in CLDN10 have been linked to HELIX syndrome,a salt-losing tubulopathy with altered handling of divalent cations accompanied by dysfunctional salivary,sweat,and lacrimal glands.Here,we investigate molecular basis and phenotypic consequences of a newly identified homozygous CLDN10 variant that translates into a single amino acid substitution within the fourth transmembrane helix of claudin-10.In addition to hypohidrosis(H),electrolyte(E)imbalance with impaired urine concentrating ability,and hypolacrimia(L),phenotypic findings include altered salivary electrolyte composition and amelogenesis imperfecta but neither ichthyosis(I)nor xerostomia(X).Employing cellular TJ reconstitution assays,we demonstrate perturbation of cis-and trans-interactions between mutant claudin-10 proteins.Ultrastructures of reconstituted TJ strands show disturbed continuity and reduced abundance in the mutant case.Throughout,both major isoforms,claudin-10a and claudin-10b,are differentially affected with claudin-10b showing more severe molecular alterations.However,expression of the mutant in renal epithelial cells with endogenous TJs results in wild-type-like ion selectivity and conductivity,indicating that aberrant claudin-10 is generally capable of forming functional paracellular channels.Thus,mutant proteins prove pathogenic by compromising claudin-10 TJ strand assembly.Additional ex vivo investigations indicate their insertion into TJs to occur in a tissue-specific manner.展开更多
基金supported by grants from NINDS R01NS066927Department of Veterans Affairs R&D funds
文摘Genetic factors may be learnt from families with gene mutations that render nerve-injury sus- ceptibility even to ordinary physical activities. A typical example is hereditary neuropathy with liability to pressure palsies （HNPP）. HNPP is caused by a heterozygous deletion of PMP22 gene. PMP22 deficiency disrupts myelin junctions （such as tight junction and adherens junctions）, leading to abnormally increased myelin permeability that explains the nerve susceptibility to injury. This finding should motivate investigators to identify additional genetic factors contribut- ing to nerve vulnerability of injury.
文摘AIM: To develop a risk model for Crohn’s disease (CD) based on homogeneous population.METHODS: In our study were included 160 CD patients and 209 healthy individuals from Slovenia. The association study was performed for 112 single nucleotide polymorphisms (SNPs). We generated genetic risk scores (GRS) based on the number of risk alleles using weighted additive model. Discriminatory accuracy was measured by area under ROC curve (AUC). For risk evaluation, we divided individuals according to positive and negative likelihood ratios (LR) of a test, with LR > 5 for high risk group and LR < 0.20 for low risk group.RESULTS: The highest accuracy, AUC of 0.78 was achieved with GRS combining 33 SNPs with optimal sensitivity and specificity of 75.0% and 72.7%, respectively. Individuals with the highest risk (GRS > 5.54) showed significantly increased odds of developing CD (OR = 26.65, 95%CI: 11.25-63.15) compared to the individuals with the lowest risk (GRS < 4.57) which is a considerably greater risk captured than in one SNP with the highest effect size (OR = 3.24). When more than 33 SNPs were included in GRS, discriminatory ability was not improved significantly; AUC of all 74 SNPs was 0.76.CONCLUSION: The authors proved the possibility of building accurate genetic risk score based on 33 risk variants on Slovenian CD patients which may serve as a screening tool in the targeted population.
文摘Background: The inadequacy in the completeness of the Laboratory Request Form (LRF) has been reported as one of the major sources of errors during the pre-analytical step of laboratory analysis. To prevent the occurrence of such errors, this study aimed at assessing the level of completeness of LRFs. Methods: A retrospective analysis of laboratory request forms was conducted at the Clinical Biology Laboratory of the Kinshasa University Clinic, DR Congo, between November 2021 to May 2022. The LRFs were evaluated according to the completeness of all sections including administrative data of the patient, data of physician who ordered the test, relevant patient’s clinical data and data of the biological sample. Results: From a total of 2842 LRFs evaluated, none was fully completed with all required information. Particularly, patient’s clinical data including the medical history, provisional diagnosis and current treatment, were the most absent in 99% LRFs. However, two sections related to patient’s ID and prescribed test were informed in 100% LRFs. Conclusion: The results of this preanalytical audit can serve as an improvement opportunity focused on strengthening awareness about complete filling of LRF.
基金the Chinese National Natural Science Foundation(No.8 1000346,Y.G.Y.)foundation grant from the Center for Clinical Nutrition Study(SCMC-YP-HOPE-KY-0905 for Y.G.Y)+5 种基金Health Science grant from the social development branch of Pudong New District(PW2009D-9 for Y.G.Y)the Simons Foundation(J.F.G.)Autism Speaks(J.F.G.)Developmental Genome Anatomy Project(P01 GM061354)Chinese National"973"Project on Population and Health(No.2010CB529601,B.-L.W.)Science and Technology Council of Shanghai(No.09JC1402400(B.-L.W.)
文摘Recurrent genomic imbalances at 16p 11.2 are genetic risk factors of variable penetrance for developmental delay and autism.Recently, 16pl 1.2（chr16：29.5 Mb-30.1 Mb） deletion has also been detected in individuals with early-onset severe obesity.The penetrance of 16p11.2 deletion as a genetic risk factor for obesity is unknown.We evaluated the growth and body mass characteristics of 28 individuals with 16p11.2 （chr16：29.5 Mb-30.1 Mb） deletion originally ascertained for their developmental disorders by reviewing their medical records.We found that nine individuals could be classified as obese and six as overweight.These individuals generally had early feeding and growth difficulties,and started to gain excessive weight around 5-6 years of age.Thirteen out of the 18 deletion carriers aged 5 years and older（72%） were overweight or obese,whereas only two of 10 deletion carriers（20%） younger than five were overweight or obese.Males exhibited more severe obesity than females.Thus,the obesity phenotype of 16p11.2 deletion carriers is of juvenile onset,exhibited an age- and gender-dependent penetrance. 16p11.2 deletion appears to predispose individuals to juvenile onset obesity and in this case are similar to the well-described Prader-Willi syndrome（PWS）.Early detection of this deletion will provide opportunity to prevent obesity.
文摘Objective: Pelvic organ prolapse is an emerging public health problem affecting adult women of all ages with a negative impact on social, physical well-being, and psychological. Its presents several challenges in countries with low resources. This literature review aims to examine POP in its epidemiological aspects, risk factors, and staging by taking up the challenges associated with low-resource settings and identifying some avenues for future research. Methods: We searched the PubMed, Google Scholar, and Scopus databases. The other studies were identified by checking the secondary references in the original citation. We have collected studies on adult women published in English for the last 30 years. In total, 71 articles were read. We excluded studies from all newspaper articles, Studies presenting co-morbidities (fistulas, cervical cancer, pregnancy), those evaluating treatment, letters, comments, case reports, practice guidelines, news, historical articles, legal cases, published erratum, and congresses. Results: 16 studies examining the epidemiology have been identified with 11 in countries defined by the World Bank as limited or intermediate resources. 18 on risk factors whose 10 in countries with limited or intermediate resources, 10 on staging and 27 on physiopathology. Conclusion: POP affects the young more in low-resource settings. Its prevalence remains underestimated for several reasons. Several risk factors found are the same as those of women in countries with a high standard of living. However, there are some specific risk factors for these resource-limited settings.
基金Supported by the Zhejiang Provincial Educational Bureau Foundation,China(Y201223905)
文摘AIM:To study the associations between lysyl oxidaselike 1(LOXL1)polymorphisms and primary open angle glaucoma(POAG)remain inconsistent.In this study,we have performed a meta-analysis to investigate the association of LOXL1 polymorphisms with POAG risk.METHODS:Published literature from PubMed and other databases were retrieved.All studies evaluating the association between LOXL1 polymorphisms(rs2165241,rs1048661,rs3825942)and POAG risk were included.Pooled odds ratio(OR)and 95%confidence interval(CI)were calculated using random-or fixed-effects model.RESULTS:Twelve studies were identified as eligible articles,with thirteen(2098 cases and 16 473 controls),thirteen(1795 cases and 2916 controls)and sixteen population cohorts(2456 cases and 2846 controls)for the association of rs2165241,rs1048661 and rs3825942with POAG risk respectively.Overall analyses showed noassociation between each LOXL1 polymorphism and POAG risk,and the negative associations were remained when the subjects were stratified as Caucasian and Asian.The heterozygote of rs2165241 was associated with reduced POAG risk in hospital-based populations(TC vs CC:OR,0.79,95%CI:0.63-0.99),and rs1048661was associated with increased POAG risk in hospitalbased populations in a dominant model(TT vs CC+CT:OR,1.23,95%CI:1.01-1.50);however,these associations were not found in population-based subjects.CONCLUSION:This meta-analysis suggests that LOXL1 polymorphisms are not associated with POAG risk.Given the limited sample size,the associations of LOXL1 polymorphisms with POAG risk in hospital-based populations await further investigation.
文摘wide association studies(GWAS)in recent years.Since the identification of variants in the complement factor H gene on the risk of age-related macular degeneration,GWAS have become ubiquitous in genetic studies and have led to the identification of genetic variants that are associated with a variety of complex human diseases and traits.These discoveries have changed our understanding of the biological architecture of common,complex diseases and have also provided new hypotheses to test.New tools,such as next-generation sequencing,will be an important part of the future of genetics research;however,GWAS studies will continue to play an important role in disease gene discovery.Many traits have yet to be explored by GWAS,especially in minority populations,and large collaborative studies are currently being conducted to maximize the return from existing GWAS data.In addition,GWAS technology continues to improve,increasing genomic coverage for major global populations and decreasing the cost of experiments.Although much of the variance attributable to genetic factors for many important traits is still unexplained,GWAS technology has been instrumental in mapping over a thousand genes to hundreds of traits.More discoveries are made each month and the scale,quality and quantity of current work has a steady trend upward.We briefly review the current key trends in GWAS,which can be summarized with three goals:increase power,increase collaborations and increase populations.
文摘Sickle cell anemia (SCA) is an autosomal-recessive hemoglobinopathy with a highly variable phenotype. Multiple clinical complications are characteristic of SCA including inflammatory and oxidant damage to both small and large blood vessels, hemolysis, vasoocclusion, and premature mortality. The overall severity of SCA is affected by multiple genetic modifier loci, including ARFGEF2, a gene known to modify TNF-α receptor release from human endothelial cells. In this report, we examine the effect of siRNA mediated knockdown of ARFGEF2 inhuman pulmonary artery endothelial cells and report that TNF-α induced expression of ICAM1 and VCAM1, both important mediators of endo-thelial-leukocyte adhesion, is significantly enhanced after ARFGEF2 knockdown. Levels of ICAM-1 protein are also increased in TNF-α treated endothelial cells after ARFGEF2 knockdown;the increased ICAM-1 appears to be localized in the cytoplasm. IL-1β stimulation of endothelial cells without ARFGEF2 produced enhanced ICAM1 expression only. Additionally, ARFGEF2 knockdown distinctly altered endothelial cell morphology. Large-vessel pathology in SCA is believed to begin with endothelial activation by inflammatory cytokines and adhesion of sickle erythrocytes and leukocytes, leading to a progressive vasculopathy characterized by smooth muscle cell migration and proliferation. Understanding how variability in the function of ARFGEF2 alters the response of pulmonary vasculature to TNF-α might suggest new targets for SCA treatment.
文摘Objective: Charcot-Marie-Tooth (CMT) neuropathy with visual impairment due to optic atrophy has been designated as hereditary motor and sensory neuropathy type VI (HMSN VI). Reports of affected families have indicated autosomal dominant and recessive forms,but the genetic cause of this disease has remained elusive. Methods:Here,we describe six HMSN VI families with a subacute onset of optic atrophy and subsequent slow recovery of visual acuity in 60% of the patients. Detailed clinical and genetic studies were performed. Results: In each pedigree,we identified a unique mutation in the gene mitofusin 2 (MFN2). In three families,the MFN2 mutation occurred de novo; in two families the mutation was subsequently transmitted from father to son indicating autosomal dominant inheritance. Interpretation: MFN2 is a mitochondrial membrane protein that was recently reported to cause axonal CMT type 2A. It is intriguing that MFN2 shows functional overlap with optic atrophy 1 (OPA1),the protein underlying the most common form of autosomal dominant optic atrophy,and mitochondrial encoded oxidative phosphorylation components as seen in Leber’ s hereditary optic atrophy. We conclude that autosomal dominant HMSN VI is caused by mutations in MFN2,emphasizing the important role of mitochondrial function for both optic atrophies and peripheral neuropathies.
基金financially supported by Interface Biotech A/S,Horsholm,Denmark.
文摘The purpose of this study was to perform morphological and molecular analyses of articular cartilage from a 14-year-old boy with unusual cartilage lesions, patella alta and trochlea dysplasia in both knee joints and clinically examine two family members (sister, mother), also affected in their knee joints. Biopsies from the boy’s patella were used for: histological examination, Transmission Electron Microscopy (TEM) and DNA sequencing of the COL2A1 gene including Multiplex Ligation-dependent Probe Amplification (MLPA), for detection of DNA deletions and duplications. Clinical and radiological examination showed patella alta and trochlea dysplasia for the brother (type D), sister (type A) and mother (type A) with Insall-Salvati ratios of 1.50, 1.46 and 1.3. Light Microscopy (LM) of biopsies from the patient showed rhomboid chondrocytes in lacuna with deposition of protein aggregates in the ECM. TEM revealed abnormal type II collagen fibrils in aggregates and chondrocytes with abnormal matrix accumulation in rough Endoplasmic Reticulum (rER). Immunostaining showed that type II collagen was deposited intracellularly and in protein aggregates, together with type I collagen, indicating alterations in chondrocyte function and turnover of these molecules. DNA sequencing of 54 exons including extended DNA analysis with MLPA was non-conclusive. Conclusions: We suggest that patella alta and trochlea dysplasia for this patient is associated with collagen accumulation in chondrocytes, abnormal type II collagen heterofibrils in the ECM, cell death and cartilage with subnormal strength and increased risk of premature patellofemoral arthritis. A family with these disorders suggests that phenotype might be transmitted as an autosomal dominant trait.
基金funding from the Strategic Priority Research Program of the Chinese Academy of Sciences(XDPB17)National Key Research and Development Program of China(2020YFA0712402)+2 种基金the National Natural Science Foundation of China(grants 12025107,11871463,61621003,11688101)The Genotype-Tissue Expression(GTEx)Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health,and by NCI,NHGRI,NHLBI,NIDA,NIMH,and NINDSThe data used for the analyses described in this manuscript were obtained from the GTEx Portal under dbGaP accession number phs000424.v8.p2 on 12/09/2020.
文摘Human genetic variants can influence the severity of symptoms infected with SARS-COV-2.Several genome-wide asso-ciation studies have identified human genomic risk single nucleotide polymorphisms(SNPs)associated with coronavirus disease 2019(COVID-19)severity.However,the causal tissues or cell types underlying COVID-19 severity are uncertain.In addition,candidate genes associated with these risk SNPs were investigated based on genomic proximity instead of their functional cellular contexts.Here,we compiled regulatory networks of 77 human contexts and revealed those risk SNPs’enriched cellular contexts and associated risk SNPs with transcription factors,regulatory elements,and target genes.Twenty-one human contexts were identified and grouped into two categories:immune cells and epithelium cells.We further aggregated the regulatory networks of immune cells and epithelium cells.These two aggregated regulatory networks were investigated to reveal their association with risk SNPs’regulation.Two genomic clusters,the chemokine receptors cluster and the oligoadenylate synthetase(OAS)cluster,showed the strongest association with COVID-19 severity,and they had different regulatory programs in immune and epithelium contexts.Our findings were supported by analysis of both SNP array and whole genome sequencing-based genome wide association study(GWAS)summary statistics.
文摘目的通过对无精症患者异常染色体及Y染色体（Yqll．2区段）无精症因子（azoospermic fac—tor，AZF）微缺失的分析，探讨无精症与染色体异常的关系。方法对25例原因不明的无精症患者进行G带染色体核型分析、荧光口显带、荧光原位杂交（fluorescence in situ hybridization，FISH）和AZF微缺失PCR检测。结果25例原因不明的无精症患者中染色体核型异常7例，异常发生率为28％；对8例无精症患者进行AZF微缺失检测：AZF区微缺失2例，分别为AZFb（SYl27，SYl34）＋AZFc（SY254，SY255）缺失、AZFc（SY243，SYl58）缺失。结论染色体异常及Y染色体AZF微缺失是引起无精症并造成男性不育的重要原因之一，对无精症等不育男性患者在排除睾丸病变、阻塞性无精症、内分泌及免疫系统等临床病理学因素后，包括配偶有不明原因习惯性流产的男性均需做外周血染色体常规GTG-显带、荧光Q-显带检查。Q-带阴性的患者说明其Y染色体长臂缺失的断裂点高于Yql2，在Yqll．2区段，则需要结合FISH和AZF微缺失的PCR检测，以确诊Y染色体的微缺失区段，为患者的临床进一步治疗提供可靠的依据。
文摘Background:There are several clinical reports about the co-occurrence of autosomal dominant polycystic kidney disease(ADPKD)and connective tissue disorders.A simultaneous occurrence of osteogenesis imperfecta(OI)type I and ADPKD has not been observed so far.Methods:This report presents the first patient with OI type I and ADPKD.Results:Mutational analysis of PKD1 and COL1A1 in the index patient revealed a heterozygous mutation in each of the two genes.Mutational analysis of the parents indicated the mother as a carrier of the PKD1 mutation and the father as a carrier of the COL1A1 mutation.The simultaneous occurrence of both disorders has an estimated frequency of 3.5:100000000.Conclusion:In singular cases,ADPKD can occur in combination with other rare disorders,e.g.connective tissue disorders.
基金supported by Deutsche Forschungsgemeinschaft(DFG)grants(No.GU 447/14-1,14-2 to DG,PI 837/4-1,4-2 to JP,and(No.HA 6908/2-1 to JH,respectively)by Else Kroner-Fresenius-Stiftung grant(No.2016_A52 to JH)+3 种基金JH receives additional funding from the DFG(No.6908/3-1)CB is an employee of Limbach and holds a part-time faculty appointment at the University of FreiburgHis research laboratory receives support from the DFG(No.BE 3910/8-1 and BE 3910/9-1)from the Federal Ministry of Education and Research(BMBF,No.01GM1903I and 01GM1903G).
文摘Formation of claudin-10 based tight junctions(TJs)is paramount to paracellular Na+transport in multiple epithelia.Sequence variants in CLDN10 have been linked to HELIX syndrome,a salt-losing tubulopathy with altered handling of divalent cations accompanied by dysfunctional salivary,sweat,and lacrimal glands.Here,we investigate molecular basis and phenotypic consequences of a newly identified homozygous CLDN10 variant that translates into a single amino acid substitution within the fourth transmembrane helix of claudin-10.In addition to hypohidrosis(H),electrolyte(E)imbalance with impaired urine concentrating ability,and hypolacrimia(L),phenotypic findings include altered salivary electrolyte composition and amelogenesis imperfecta but neither ichthyosis(I)nor xerostomia(X).Employing cellular TJ reconstitution assays,we demonstrate perturbation of cis-and trans-interactions between mutant claudin-10 proteins.Ultrastructures of reconstituted TJ strands show disturbed continuity and reduced abundance in the mutant case.Throughout,both major isoforms,claudin-10a and claudin-10b,are differentially affected with claudin-10b showing more severe molecular alterations.However,expression of the mutant in renal epithelial cells with endogenous TJs results in wild-type-like ion selectivity and conductivity,indicating that aberrant claudin-10 is generally capable of forming functional paracellular channels.Thus,mutant proteins prove pathogenic by compromising claudin-10 TJ strand assembly.Additional ex vivo investigations indicate their insertion into TJs to occur in a tissue-specific manner.
