Nephronophthisis(NPH),an autosomal recessive tubulo-interstitial nephropathy,is characterized by interstitial inflammation and progressive kidney fibrosis.To date,mutations in more than 25 NPHP genes have been associa...Nephronophthisis(NPH),an autosomal recessive tubulo-interstitial nephropathy,is characterized by interstitial inflammation and progressive kidney fibrosis.To date,mutations in more than 25 NPHP genes have been associated with NPH,resulting in a wide genetic heterogeneity and overlapping clinical phenotypes.展开更多
Mutations in serologically defined colon cancer autoantigen protein 8(SDCCAG8)were first identified in retinal ciliopathy families a decade ago with unknown function.To investigate the pathogenesis of SDCCAG8-associat...Mutations in serologically defined colon cancer autoantigen protein 8(SDCCAG8)were first identified in retinal ciliopathy families a decade ago with unknown function.To investigate the pathogenesis of SDCCAG8-associated retinal ciliopathies in vivo,we employed CRISPR/Cas9-mediated homology-directed recombination(HDR)to generate two knock-in mouse models,Sdccag8^(Y236X/Y236X) and Sdccag8^(E451GfsX467/E451GfsX467),which carry truncating mutations of the mouse Sdccag8,corresponding to mutations that cause Bardet-Biedl syndrome(BBS)and Senior-L?ken syndrome(SLS)(c.696T>G p.Y232X and c.1339-1340ins G p.E447GfsX463)in humans,respectively.The two mutant Sdccag8 knock-in mice faithfully recapitulated human SDCCAG8-associated BBS phenotypes such as rod-cone dystrophy,cystic renal disorder,polydactyly,infertility,and growth retardation,with varied age of onset and severity depending on the hypomorphic strength of the Sdccag8 mutations.To the best of our knowledge,these knock-in mouse lines are the first BBS mouse models to present with the polydactyly phenotype.Major phototransduction protein mislocalization was also observed outside the outer segment after initiation of photoreceptor degeneration.Impaired cilia were observed in the mutant photoreceptors,renal epithelial cells,and mouse embryonic fibroblasts derived from the knock-in mouse embryos,suggesting that SDCCAG8 plays an essential role in ciliogenesis,and cilium defects are a primary driving force of SDCCAG8-associated retinal ciliopathies.展开更多
Nephronophthisis(NPHP)is an autosomal recessive kidney disease and is the most prevalent monogenic cause of end-stage renal disease in childhood.The tetratricopeptide repeat domain 21B(TTC21B)gene encodes the ciliary ...Nephronophthisis(NPHP)is an autosomal recessive kidney disease and is the most prevalent monogenic cause of end-stage renal disease in childhood.The tetratricopeptide repeat domain 21B(TTC21B)gene encodes the ciliary protein intraflagellar transport protein 139(IFT139)and has been recently implicated in heterogeneous diseases,including nephronophthisis type 12(NPHP12),short-rib thoracic dysplasia 4(SRTD4).展开更多
Kidney disease is manifested in a wide variety of phenotypes,many of which have an important hereditary component.To delineate the genotypic and phenotypic spectrum of pediatric nephropathy,a multicenter registration ...Kidney disease is manifested in a wide variety of phenotypes,many of which have an important hereditary component.To delineate the genotypic and phenotypic spectrum of pediatric nephropathy,a multicenter registration system is being imple-mented based on the Chinese Children Genetic Kidney Disease Database(CCGKDD).In this study,all the patients with kidney and urological diseases were recruited from 2014 to 2020.Genetic analysis was conducted using exome sequencing for families with multiple affected individuals with nephropathy or clinical suspicion of a genetic kidney disease owing to early-onset or extrarenal features.The genetic diagnosis was confirmed in 883 of 2256(39.1%)patients from 23 provinces in China.Phenotypic profiles showed that the primary diagnosis included steroid-resistant nephrotic syndrome(SRNS,23.5%),glomerulonephritis(GN,32.2%),congenital anomalies of the kidney and urinary tract(CAKUT,21.2%),cystic renal disease(3.9%),renal calcinosis/stone(3.6%),tubulopathy(9.7%),and chronic kidney disease of unknown etiology(CKDu,5.8%).The pathogenic variants of 105 monogenetic disorders were identified.Ten distinct genomic disorders were identified as pathogenic copy number variants(CNVs)in 11 patients.The diagnostic yield differed by subgroups,and was highest in those with cystic renal disease(66.3%),followed by tubulopathy(58.4%),GN(57.7%),CKDu(43.5%),SRNS(29.2%),renal calcinosis/stone(29.3%)and CAKUT(8.6%).Reverse phenotyping permitted correct identification in 40 cases with clinical reassessment and unexpected genetic conditions.We present the results of the largest cohort of children with kidney disease in China where diagnostic exome sequencing was performed.Our data demonstrate the utility of family-based exome sequencing,and indicate that the combined analysis of genotype and phenotype based on the national patient registry is pivotal to the genetic diagnosis of kidney disease.展开更多
基金supported by the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie Innovative Training Networks SCILS(No.861329)the Ministere de l’Education Nationale,de la Recherche et de la Technologie(MENRT)+3 种基金supported by the Deutsche Forschungsgemeinschaft(DFG,Nos.KU-1504/8-1,KU-1504/9-1,DFG CRC 1453)supported by the EMBO(No.ALTF927-2013)support from the Institut National de la Santeet de la Recherche Me´dicale(INSERM),the MENRT and the Agence Nationale de la Recherche(ANR,Nos.ANR-10-IAHU-01,ANR 17-RHUS-0002)supported by the ERAEDTA(No.ALTF84-2011).
文摘Nephronophthisis(NPH),an autosomal recessive tubulo-interstitial nephropathy,is characterized by interstitial inflammation and progressive kidney fibrosis.To date,mutations in more than 25 NPHP genes have been associated with NPH,resulting in a wide genetic heterogeneity and overlapping clinical phenotypes.
基金supported by the Natural Science Foundation of China(81670893,82121003)Science and Technology Department of Sichuan Province(2021JDZH0031)Chinese Academy of Medical Sciences(2019-I2M-5-032)。
文摘Mutations in serologically defined colon cancer autoantigen protein 8(SDCCAG8)were first identified in retinal ciliopathy families a decade ago with unknown function.To investigate the pathogenesis of SDCCAG8-associated retinal ciliopathies in vivo,we employed CRISPR/Cas9-mediated homology-directed recombination(HDR)to generate two knock-in mouse models,Sdccag8^(Y236X/Y236X) and Sdccag8^(E451GfsX467/E451GfsX467),which carry truncating mutations of the mouse Sdccag8,corresponding to mutations that cause Bardet-Biedl syndrome(BBS)and Senior-L?ken syndrome(SLS)(c.696T>G p.Y232X and c.1339-1340ins G p.E447GfsX463)in humans,respectively.The two mutant Sdccag8 knock-in mice faithfully recapitulated human SDCCAG8-associated BBS phenotypes such as rod-cone dystrophy,cystic renal disorder,polydactyly,infertility,and growth retardation,with varied age of onset and severity depending on the hypomorphic strength of the Sdccag8 mutations.To the best of our knowledge,these knock-in mouse lines are the first BBS mouse models to present with the polydactyly phenotype.Major phototransduction protein mislocalization was also observed outside the outer segment after initiation of photoreceptor degeneration.Impaired cilia were observed in the mutant photoreceptors,renal epithelial cells,and mouse embryonic fibroblasts derived from the knock-in mouse embryos,suggesting that SDCCAG8 plays an essential role in ciliogenesis,and cilium defects are a primary driving force of SDCCAG8-associated retinal ciliopathies.
基金supported by the National Natural Science Foundation of China(No.81873596)the Key Research and Development Program of Hubei Province,China(No.2022BCA047)the National Key Research and Development Program of China(No.2022YFC2705102 and No.2022YFC2705103).
文摘Nephronophthisis(NPHP)is an autosomal recessive kidney disease and is the most prevalent monogenic cause of end-stage renal disease in childhood.The tetratricopeptide repeat domain 21B(TTC21B)gene encodes the ciliary protein intraflagellar transport protein 139(IFT139)and has been recently implicated in heterogeneous diseases,including nephronophthisis type 12(NPHP12),short-rib thoracic dysplasia 4(SRTD4).
基金J.R.is supported by National Natural Science Foundation of China(NSFC-8182207)Shanghai Academic/Technology Research Leader(19XD1420600)Chinese Academy of Medical Sciences(2019-RC-HL_020).
文摘Kidney disease is manifested in a wide variety of phenotypes,many of which have an important hereditary component.To delineate the genotypic and phenotypic spectrum of pediatric nephropathy,a multicenter registration system is being imple-mented based on the Chinese Children Genetic Kidney Disease Database(CCGKDD).In this study,all the patients with kidney and urological diseases were recruited from 2014 to 2020.Genetic analysis was conducted using exome sequencing for families with multiple affected individuals with nephropathy or clinical suspicion of a genetic kidney disease owing to early-onset or extrarenal features.The genetic diagnosis was confirmed in 883 of 2256(39.1%)patients from 23 provinces in China.Phenotypic profiles showed that the primary diagnosis included steroid-resistant nephrotic syndrome(SRNS,23.5%),glomerulonephritis(GN,32.2%),congenital anomalies of the kidney and urinary tract(CAKUT,21.2%),cystic renal disease(3.9%),renal calcinosis/stone(3.6%),tubulopathy(9.7%),and chronic kidney disease of unknown etiology(CKDu,5.8%).The pathogenic variants of 105 monogenetic disorders were identified.Ten distinct genomic disorders were identified as pathogenic copy number variants(CNVs)in 11 patients.The diagnostic yield differed by subgroups,and was highest in those with cystic renal disease(66.3%),followed by tubulopathy(58.4%),GN(57.7%),CKDu(43.5%),SRNS(29.2%),renal calcinosis/stone(29.3%)and CAKUT(8.6%).Reverse phenotyping permitted correct identification in 40 cases with clinical reassessment and unexpected genetic conditions.We present the results of the largest cohort of children with kidney disease in China where diagnostic exome sequencing was performed.Our data demonstrate the utility of family-based exome sequencing,and indicate that the combined analysis of genotype and phenotype based on the national patient registry is pivotal to the genetic diagnosis of kidney disease.
