Neurodevelopmental disorders(NDDs)are a set of complex disorders characterized by diverse and cooccurring clinical symptoms.The genetic contribution in patients with NDDs remains largely unknown.Here,we sequence 519 N...Neurodevelopmental disorders(NDDs)are a set of complex disorders characterized by diverse and cooccurring clinical symptoms.The genetic contribution in patients with NDDs remains largely unknown.Here,we sequence 519 NDD-related genes in 3,195 Chinese probands with neurodevelopmental phenotypes and identify 2,522 putative functional mutations consisting of 137 de novo mutations(DNMs)in 86 genes and 2,385 rare inherited mutations(RIMs)with 22 X-linked hemizygotes in 13 genes,2 homozygous mutations in 2 genes and 23 compound heterozygous mutations in 10 genes.Furthermore,the DNMs of16,807 probands with NDDs are retrieved from public datasets and combine in an integrated analysis with the mutation data of our Chinese NDD probands by taking 3,582 in-house controls of Chinese origin as background.We prioritize 26 novel candidate genes.Notably,six of these genes d ITSN1,UBR3,CADM1,RYR3,FLNA,and PLXNA3 d preferably contribute to autism spectrum disorders(ASDs),as demonstrated by high co-expression and/or interaction with ASD genes confirmed via rescue experiments in a mouse model.Importantly,these genes are differentially expressed in the ASD cortex in a significant manner and involved in ASD-associated networks.Together,our study expands the genetic spectrum of Chinese NDDs,further facilitating both basic and translational research.展开更多
The serine/threonine p21-activated kinases(PAKs),as main effectors of the Rho GTPases Cdc42 and Rac,represent a group of important molecular switches linking the complex cytoskeletal networks to broad neural activity....The serine/threonine p21-activated kinases(PAKs),as main effectors of the Rho GTPases Cdc42 and Rac,represent a group of important molecular switches linking the complex cytoskeletal networks to broad neural activity.PAKs show wide expression in the brain,but they differ in specific cell types,brain regions,and developmental stages.PAKs play an essential and differential role in controlling neural cytoskeletal remodeling and are related to the development and fate of neurons as well as the structural and functional plasticity of dendritic spines.PAK-mediated actin signaling and interacting functional networks represent a common pathway frequently affected in multiple neurodevelopmental and neurodegenerative disorders.Considering specific small-molecule agonists and inhibitors for PAKs have been developed in cancer treatment,comprehensive knowledge about the role of PAKs in neural cytoskeletal remodeling will promote our understanding of the complex mechanisms underlying neurological diseases,which may also represent potential therapeutic targets of these diseases.展开更多
基金supported by the Guangdong Key Project in“Development of new tools for diagnosis and treatment of Autism”(2018B030335001 to Z.Sun)and“Early diagnosis and treatment of autism spectrum disorders”(202007030002 to Z.Sun)the National Natural Science Foundation of China(32070590 to Y.Wang)+5 种基金the National Natural Science Foundation of China(81730036 and81525007 to K.Xia)Science and Technology Major Project of Hunan Provincial Science and Technology Department(2018SK1030 to K.Xia)the National Natural Science Foundation of China(81801133 to J.Li)the Young Elite Scientist Sponsorship Program by CAST(2018QNRC001 to J.Li)the Innovation-Driven Project of Central South University(20180033040004 to J.Li)Natural Science Foundation of Hunan Province for outstanding Young Scholars(2020JJ3059 to J.Li)。
文摘Neurodevelopmental disorders(NDDs)are a set of complex disorders characterized by diverse and cooccurring clinical symptoms.The genetic contribution in patients with NDDs remains largely unknown.Here,we sequence 519 NDD-related genes in 3,195 Chinese probands with neurodevelopmental phenotypes and identify 2,522 putative functional mutations consisting of 137 de novo mutations(DNMs)in 86 genes and 2,385 rare inherited mutations(RIMs)with 22 X-linked hemizygotes in 13 genes,2 homozygous mutations in 2 genes and 23 compound heterozygous mutations in 10 genes.Furthermore,the DNMs of16,807 probands with NDDs are retrieved from public datasets and combine in an integrated analysis with the mutation data of our Chinese NDD probands by taking 3,582 in-house controls of Chinese origin as background.We prioritize 26 novel candidate genes.Notably,six of these genes d ITSN1,UBR3,CADM1,RYR3,FLNA,and PLXNA3 d preferably contribute to autism spectrum disorders(ASDs),as demonstrated by high co-expression and/or interaction with ASD genes confirmed via rescue experiments in a mouse model.Importantly,these genes are differentially expressed in the ASD cortex in a significant manner and involved in ASD-associated networks.Together,our study expands the genetic spectrum of Chinese NDDs,further facilitating both basic and translational research.
基金This work was supported by the National Natural Science Foundation of China(Nos.32070590 and 31871191)the Guangdong Key Project in the“development of new tools for diagnosis and treatment of Autism”(2018B030335001).
文摘The serine/threonine p21-activated kinases(PAKs),as main effectors of the Rho GTPases Cdc42 and Rac,represent a group of important molecular switches linking the complex cytoskeletal networks to broad neural activity.PAKs show wide expression in the brain,but they differ in specific cell types,brain regions,and developmental stages.PAKs play an essential and differential role in controlling neural cytoskeletal remodeling and are related to the development and fate of neurons as well as the structural and functional plasticity of dendritic spines.PAK-mediated actin signaling and interacting functional networks represent a common pathway frequently affected in multiple neurodevelopmental and neurodegenerative disorders.Considering specific small-molecule agonists and inhibitors for PAKs have been developed in cancer treatment,comprehensive knowledge about the role of PAKs in neural cytoskeletal remodeling will promote our understanding of the complex mechanisms underlying neurological diseases,which may also represent potential therapeutic targets of these diseases.
