AIM： To map Usher phenotype in a consanguineous Pakistani family and identify disease-associated mutation in a causative gene to establish phenotype-genotype correlation.· METHODS： A consanguineous Pakistani fa...AIM： To map Usher phenotype in a consanguineous Pakistani family and identify disease-associated mutation in a causative gene to establish phenotype-genotype correlation.· METHODS： A consanguineous Pakistani family in which Usher phenotype was segregating as an autosomal recessive trait was ascertained. On the basis of results of clinical investigations of affected members of this family disease was diagnosed as Usher syndrome（USH）. To identify the locus responsible for the Usher phenotype in this family, genomic DNA from blood sample of each individual was genotyped using microsatellite Short Tandem Repeat（STR） markers for the known Usher syndrome loci. Then direct sequencing was performed to find out disease associated mutations in the candidate gene.· RESULTS： By genetic linkage analysis, the USH phenotype of this family was mapped to PCDH15 locus on chromosome 10q21.1. Three different point mutations in exon 11 of PCDH15 were identified and one of them,c.1304AC was found to be segregating with the disease phenotype in Pakistani family with Usher phenotype.This, c.1304 A C transversion mutation predicts an amino-acid substitution of aspartic acid with an alanine at residue number 435（p.D435A） of its protein product.Moreover, in silico analysis revealed conservation of aspartic acid at position 435 and predicated this change as pathogenic.·CONCLUSION：Theidentificationofc.1304ACpathogenic mutation in PCDH15 gene and its association with Usher syndrome in a consanguineous Pakistani family is thefirst example of a missense mutation of PCDH15 causing USH1 phenotype. In previous reports, it was hypothesized that severe mutations such as truncated protein of PCDH15 led to the Usher I phenotype and that missense variants are mainly responsible for non-syndromic hearing impairment.展开更多
Hereditary spastic paraplegias(HSPs)refer to a genetically and clinically heterogeneous group of neurodegenerative disorders characterized by the degeneration of motor neurons.To date,a significant number of patients ...Hereditary spastic paraplegias(HSPs)refer to a genetically and clinically heterogeneous group of neurodegenerative disorders characterized by the degeneration of motor neurons.To date,a significant number of patients still have not received a definite genetic diagnosis.Therefore,identifying unreported causative genes continues to be of great importance.Here,we perform whole-exome sequencing in a cohort of Chinese HSP patients.Three homozygous variants(p.L604W,p.S517F,and p.T984A)within the sterol regulatory element-binding factor 2(SREBF2)gene are identified in one autosomal recessive family and two sporadic patients,respectively.Co-segregation is confirmed by Sanger sequencing in all available members.The three variants are rare in the public or in-house database and are predicted to be damaging.The biological impacts of variants in SREBF2 are examined by functional experiments in patient-derived fibroblasts and Drosophila.We find that the variants upregulate cellular cholesterol due to the overactivation of SREBP2,eventually impairing the autophagosomal and lysosomal functions.The overexpression of the mature form of SREBP2 leads to locomotion defects in Drosophila.Our findings identify SREBF2 as a causative gene for HSP and highlight the impairment of cholesterol as a critical pathway for HSP.展开更多
Primary familial brain calcification(PFBC)is an inherited neurodegenerative disorder mainly characterized by progressive calcium deposition bilaterally in the brain,accompanied by various symptoms,such as dystonia,ata...Primary familial brain calcification(PFBC)is an inherited neurodegenerative disorder mainly characterized by progressive calcium deposition bilaterally in the brain,accompanied by various symptoms,such as dystonia,ataxia,parkinsonism,dementia,depression,headaches,and epilepsy.Currently,the etiology of PFBC is largely unknown,and no specific prevention or treatment is available.During the past 10 years,six causative genes(SLC20A2,PDGFRB,PDGFB,XPR1,MYORG,and JAM2)have been identified in PFBC.In this review,considering mechanistic studies of these genes at the cellular level and in animals,we summarize the pathogenesis and potential preventive and therapeutic strategies for PFBC patients.Our systematic analysis suggests a classification for PFBC genetic etiology based on several characteristics,provides a summary of the known composition of brain calcification,and identifies some potential therapeutic targets for PFBC.展开更多
Autism spectrum disorders(ASD) are a pervasive neurodevelopmental disease characterized by deficits in social interaction and nonverbal communication, as well as restricted interests and stereotypical behavior. Geneti...Autism spectrum disorders(ASD) are a pervasive neurodevelopmental disease characterized by deficits in social interaction and nonverbal communication, as well as restricted interests and stereotypical behavior. Genetic changes/heritability is one of the major contributing factors, and hundreds to thousands of causative and susceptible genes, copy number variants(CNVs), linkage regions, and micro RNAs have been associated with ASD which clearly indicates that ASD is a complex genetic disorder. Here, we will briefly summarize some of the high-confidence genetic changes in ASD and their possible roles in their pathogenesis.展开更多
Amyotrophic lateral sclerosis(ALS)is a devastating neurodegenerative disease characterized by progressive neuronal loss and degeneration of upper motor neuron(UMN)and lower motor neuron(LMN).The clinical presentations...Amyotrophic lateral sclerosis(ALS)is a devastating neurodegenerative disease characterized by progressive neuronal loss and degeneration of upper motor neuron(UMN)and lower motor neuron(LMN).The clinical presentations of ALS are heterogeneous and there is no single test or procedure to establish the diagnosis of ALS.Most cases are diagnosed based on symptoms,physical signs,progression,EMG,and tests to exclude the overlapping conditions.Familial ALS represents about 5~10% of ALS cases,whereas the vast majority of patients are sporadic.To date,more than 20 causative genes have been identified in hereditary ALS.Detecting the pathogenic mutations or risk variants for each ALS individual is challenging.However,ALS patients carrying some specific mutations or variant may exhibit subtly distinct clinical features.Unraveling the respective genotype-phenotype correlation has important implications for the genetic explanations.In this review,we will delineate the clinical features of ALS,outline the major ALS-related genes,and summarize the possible genotype-phenotype correlations of ALS.展开更多
基金Supported by the Kohat University of Science and Technology,Kohat,PakistanInstitute of Biomedical and Genetic Engineering,Islamabad,Pakistan
文摘AIM： To map Usher phenotype in a consanguineous Pakistani family and identify disease-associated mutation in a causative gene to establish phenotype-genotype correlation.· METHODS： A consanguineous Pakistani family in which Usher phenotype was segregating as an autosomal recessive trait was ascertained. On the basis of results of clinical investigations of affected members of this family disease was diagnosed as Usher syndrome（USH）. To identify the locus responsible for the Usher phenotype in this family, genomic DNA from blood sample of each individual was genotyped using microsatellite Short Tandem Repeat（STR） markers for the known Usher syndrome loci. Then direct sequencing was performed to find out disease associated mutations in the candidate gene.· RESULTS： By genetic linkage analysis, the USH phenotype of this family was mapped to PCDH15 locus on chromosome 10q21.1. Three different point mutations in exon 11 of PCDH15 were identified and one of them,c.1304AC was found to be segregating with the disease phenotype in Pakistani family with Usher phenotype.This, c.1304 A C transversion mutation predicts an amino-acid substitution of aspartic acid with an alanine at residue number 435（p.D435A） of its protein product.Moreover, in silico analysis revealed conservation of aspartic acid at position 435 and predicated this change as pathogenic.·CONCLUSION：Theidentificationofc.1304ACpathogenic mutation in PCDH15 gene and its association with Usher syndrome in a consanguineous Pakistani family is thefirst example of a missense mutation of PCDH15 causing USH1 phenotype. In previous reports, it was hypothesized that severe mutations such as truncated protein of PCDH15 led to the Usher I phenotype and that missense variants are mainly responsible for non-syndromic hearing impairment.
基金supported by the grants from the National Natural Science Foundation of China to Zhi-Ying Wu(82230062,Beijing),Qiao Wei(82402156,Beijing),and Wanzhong Ge(31970668,Beijing)the research foundation for distinguished scholar of Zhejiang University(188020-193810101/089,Hangzhou)to Zhi-Ying Wu
文摘Hereditary spastic paraplegias(HSPs)refer to a genetically and clinically heterogeneous group of neurodegenerative disorders characterized by the degeneration of motor neurons.To date,a significant number of patients still have not received a definite genetic diagnosis.Therefore,identifying unreported causative genes continues to be of great importance.Here,we perform whole-exome sequencing in a cohort of Chinese HSP patients.Three homozygous variants(p.L604W,p.S517F,and p.T984A)within the sterol regulatory element-binding factor 2(SREBF2)gene are identified in one autosomal recessive family and two sporadic patients,respectively.Co-segregation is confirmed by Sanger sequencing in all available members.The three variants are rare in the public or in-house database and are predicted to be damaging.The biological impacts of variants in SREBF2 are examined by functional experiments in patient-derived fibroblasts and Drosophila.We find that the variants upregulate cellular cholesterol due to the overactivation of SREBP2,eventually impairing the autophagosomal and lysosomal functions.The overexpression of the mature form of SREBP2 leads to locomotion defects in Drosophila.Our findings identify SREBF2 as a causative gene for HSP and highlight the impairment of cholesterol as a critical pathway for HSP.
基金supported by the National Natural Science Foundation of China(31871262)the Shanghai Municipal Science and Technology Major Project(2018SHZDZX05)the Innovation Incentive Foundation(Center for Excellence in Brain Science and Intelligence Technology,Chinese Academy of Sciences,Shanghai,China).
文摘Primary familial brain calcification(PFBC)is an inherited neurodegenerative disorder mainly characterized by progressive calcium deposition bilaterally in the brain,accompanied by various symptoms,such as dystonia,ataxia,parkinsonism,dementia,depression,headaches,and epilepsy.Currently,the etiology of PFBC is largely unknown,and no specific prevention or treatment is available.During the past 10 years,six causative genes(SLC20A2,PDGFRB,PDGFB,XPR1,MYORG,and JAM2)have been identified in PFBC.In this review,considering mechanistic studies of these genes at the cellular level and in animals,we summarize the pathogenesis and potential preventive and therapeutic strategies for PFBC patients.Our systematic analysis suggests a classification for PFBC genetic etiology based on several characteristics,provides a summary of the known composition of brain calcification,and identifies some potential therapeutic targets for PFBC.
基金supported by National Basic Research Program of China(2011CB809102,2014CB942804,2014BAI03B01,2012YQ0302604)National Natural Science Foundation of China(31222025,31171025)+1 种基金Program for New Century Excellent Talents in University of Ministry of Education of China(ZC)the Project Sponsored by the Scientific Research Foundation for the Returned Overseas Chinese Scholars,State Education Ministry(ZC)
文摘Autism spectrum disorders(ASD) are a pervasive neurodevelopmental disease characterized by deficits in social interaction and nonverbal communication, as well as restricted interests and stereotypical behavior. Genetic changes/heritability is one of the major contributing factors, and hundreds to thousands of causative and susceptible genes, copy number variants(CNVs), linkage regions, and micro RNAs have been associated with ASD which clearly indicates that ASD is a complex genetic disorder. Here, we will briefly summarize some of the high-confidence genetic changes in ASD and their possible roles in their pathogenesis.
基金This work was supported by grants from the National Natural Science Foundation to Zhi-Ying Wu(81125009,Beijing).
文摘Amyotrophic lateral sclerosis(ALS)is a devastating neurodegenerative disease characterized by progressive neuronal loss and degeneration of upper motor neuron(UMN)and lower motor neuron(LMN).The clinical presentations of ALS are heterogeneous and there is no single test or procedure to establish the diagnosis of ALS.Most cases are diagnosed based on symptoms,physical signs,progression,EMG,and tests to exclude the overlapping conditions.Familial ALS represents about 5~10% of ALS cases,whereas the vast majority of patients are sporadic.To date,more than 20 causative genes have been identified in hereditary ALS.Detecting the pathogenic mutations or risk variants for each ALS individual is challenging.However,ALS patients carrying some specific mutations or variant may exhibit subtly distinct clinical features.Unraveling the respective genotype-phenotype correlation has important implications for the genetic explanations.In this review,we will delineate the clinical features of ALS,outline the major ALS-related genes,and summarize the possible genotype-phenotype correlations of ALS.
