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
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
Identification of disease-causing genes among a large number of candidates is a fundamental challenge in human disease studies.However,it is still time-consuming and laborious to determine the real disease-causing gen...Identification of disease-causing genes among a large number of candidates is a fundamental challenge in human disease studies.However,it is still time-consuming and laborious to determine the real disease-causing genes by biological experiments.With the advances of the high-throughput techniques,a large number of protein-protein interactions have been produced.Therefore,to address this issue,several methods based on protein interaction network have been proposed.In this paper,we propose a shortest path-based algorithm,named SPranker,to prioritize disease-causing genes in protein interaction networks.Considering the fact that diseases with similar phenotypes are generally caused by functionally related genes,we further propose an improved algorithm SPGOranker by integrating the semantic similarity of gene ontology(GO)annotations.SPGOranker not only considers the topological similarity between protein pairs in a protein interaction network but also takes their functional similarity into account.The proposed algorithms SPranker and SPGOranker were applied to 1598 known orphan disease-causing genes from 172 orphan diseases and compared with three state-of-the-art approaches,ICN,VS and RWR.The experimental results show that SPranker and SPGOranker outperform ICN,VS,and RWR for the prioritization of orphan disease-causing genes.Importantly,for the case study of severe combined immunodeficiency,SPranker and SPGOranker predict several novel causal genes.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 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 in part by the National Natural Science Foundation of China(61370024,61428209,61232001)Program for New Century Excellent Talents in University(NCET-12-0547)
文摘Identification of disease-causing genes among a large number of candidates is a fundamental challenge in human disease studies.However,it is still time-consuming and laborious to determine the real disease-causing genes by biological experiments.With the advances of the high-throughput techniques,a large number of protein-protein interactions have been produced.Therefore,to address this issue,several methods based on protein interaction network have been proposed.In this paper,we propose a shortest path-based algorithm,named SPranker,to prioritize disease-causing genes in protein interaction networks.Considering the fact that diseases with similar phenotypes are generally caused by functionally related genes,we further propose an improved algorithm SPGOranker by integrating the semantic similarity of gene ontology(GO)annotations.SPGOranker not only considers the topological similarity between protein pairs in a protein interaction network but also takes their functional similarity into account.The proposed algorithms SPranker and SPGOranker were applied to 1598 known orphan disease-causing genes from 172 orphan diseases and compared with three state-of-the-art approaches,ICN,VS and RWR.The experimental results show that SPranker and SPGOranker outperform ICN,VS,and RWR for the prioritization of orphan disease-causing genes.Importantly,for the case study of severe combined immunodeficiency,SPranker and SPGOranker predict several novel causal genes.
