Netrin-G2 is a membrane-anchored protein known to play critical roles in neuronal circuit development and synaptic organization.In this study,we identify compound heterozygous mutations of c.547delC p.(Arg183Alafs*186...Netrin-G2 is a membrane-anchored protein known to play critical roles in neuronal circuit development and synaptic organization.In this study,we identify compound heterozygous mutations of c.547delC p.(Arg183Alafs*186)and c.605G>A,p.(Trp202X)in NTNG2 causing a syndrome exhibiting developmenta delay,intellectual disability,hypotonia,and facial dysmorphism.To elucidate the underlying cellular and molecular mechanisms,CRISPR-Cas9 technology is employed to generate a knock-in mouse mode expressing the R183Afs and W202X mutations.We report that the Ntng2^(R183Afs/W202X)mice exhibit hypo tonia and impaired learning and memory.We find that the levels of CaMKII and p-GluA1^(Ser831)are decreased,and excitatory postsynaptic transmission and long-term potentiation are impaired.To increase the activity of CaMKII,the mutant mice receive intraperitoneal injections of DCP-LA,a CaMKII agonist,and show improved cognitive function.Together,our findings reveal molecular mechanisms of how NTNG2deficiency leads to impairments of cognitive ability and synaptic plasticity.展开更多
Mitochondrial diseases are caused by variants in both mitochondrial and nuclear genomes.A nuclear gene HPDL(4-hydroxyphenylpyruvate dioxygenase-like),which encodes an intermembrane mitochondrial protein,has been recen...Mitochondrial diseases are caused by variants in both mitochondrial and nuclear genomes.A nuclear gene HPDL(4-hydroxyphenylpyruvate dioxygenase-like),which encodes an intermembrane mitochondrial protein,has been recently implicated in causing a neurodegenerative disease characterized by pediatric-onset spastic movement phenotypes.Here,we report six Chinese patients with bi-allelic HPDL pathogenic variants from four unrelated families showing neuropathic symptoms of variable severity,including developmental delay/intellectual disability,spasm,and hypertonia.Seven different pathogenic variants are identified,of which five are novel.Both fibroblasts and immortalized lymphocytes derived from patients show impaired mitochondrial respiratory function,which is also observed in HPDL-knockdown(KD)He La cells.In these He La cells,overexpression of a wild-type HPDL gene can rescue the respiratory phenotype of oxygen consumption rate.In addition,a decreased activity of the oxidative phosphorylation(OXPHOS)complex II is observed in patient-derived lymphocytes and HPDL-KD He La cells,further supporting an essential role of HPDL in the mitochondrial respiratory chain.Collectively,our data expand the clinical and mutational spectra of this mitochondrial neuropathy and further delineate the possible disease mechanism involving the impairment of the OXPHOS complex II activity due to the bi-allelic inactivations of HPDL.展开更多
Dear Editor,Dilated cardiomyopathy(DCM)is a common form of inherited cardiomyopathy.In the past decades,single mutations in various genes encoding sarcomeric,cytoskeletal,and channel proteins etc.have been found to be...Dear Editor,Dilated cardiomyopathy(DCM)is a common form of inherited cardiomyopathy.In the past decades,single mutations in various genes encoding sarcomeric,cytoskeletal,and channel proteins etc.have been found to be associated with DCM(Hershberger et al.,2013;McNally and Mestroni,2017).However,the mechanisms how single mutations in sarcomeric or structural genes lead to the disease remain elusive.An interesting phenomenon often seen in familial cardiomyopathy is that different single mutations on the same gene can cause either DCM or hypertrophic cardiomyopathy(HCM)(Kathiresan and Srivastava,2012),which exhibit almost opposite disease phenotypes.DCM is characterized by thinned myocardium and septum,ventricular chamber dilation,and systolic dysfunction(Jefferies and Towbin,2010;McNally and Mestroni,2017),while HCM exhibits thickened myocardium and septum,reduced ventricular chamber,and diastolic dysfunction(Richard et al.,2003).At the cellular level,HCM cardiomyocytes exhibit concentric hypertrophy characterized by assembly of myofilaments in parallel and widening of the myocytes.In contrast,DCM cardiomyocytes show eccentric hypertrophy,with assembly of the myofilaments in series and myocyte elongation(Kehat and Molkentin,2010).展开更多
基金National Key R&D Program of China(2022YFC2703400 to Y.G.Y.)National Natural Science Foundation of China(82001209 to S.S.D.,82271904 and 82070914 to Y.G.Y.)+2 种基金Shanghai Municipal Commission of Health and Family Planning(20204Y0451 to S.S.D.)Shanghai Scientific and Technological Innovation Action Plan(20YF1440600 to S.S.D.)Shanghai Natural Science Foundation of China(21ZR1452700 to Y.K.Z.)。
文摘Netrin-G2 is a membrane-anchored protein known to play critical roles in neuronal circuit development and synaptic organization.In this study,we identify compound heterozygous mutations of c.547delC p.(Arg183Alafs*186)and c.605G>A,p.(Trp202X)in NTNG2 causing a syndrome exhibiting developmenta delay,intellectual disability,hypotonia,and facial dysmorphism.To elucidate the underlying cellular and molecular mechanisms,CRISPR-Cas9 technology is employed to generate a knock-in mouse mode expressing the R183Afs and W202X mutations.We report that the Ntng2^(R183Afs/W202X)mice exhibit hypo tonia and impaired learning and memory.We find that the levels of CaMKII and p-GluA1^(Ser831)are decreased,and excitatory postsynaptic transmission and long-term potentiation are impaired.To increase the activity of CaMKII,the mutant mice receive intraperitoneal injections of DCP-LA,a CaMKII agonist,and show improved cognitive function.Together,our findings reveal molecular mechanisms of how NTNG2deficiency leads to impairments of cognitive ability and synaptic plasticity.
基金funded by the Precision Medical Research of National Key Research and Development Program(2018YFC1002200,2019YFC1005100 to Y.Yu,2018YFC1002400 to Y.Sun,and 2018YFC1002501 to Y.Shen)National Natural Science Foundation of China(81873633 and 82071276 to Y.Shen,81830071 to J.Lyu,81873724 to Y.Sun,and 82070914 and 81873671 to Y.Yu)+7 种基金Shanghai Shen Kang Hospital Development Center(SHDC12017109 to Y.Yu)the Shanghai Science and Technology Commission(19140904500 to Y.Yu)Jiaotong University Cross Biomedical Engineering(YG2017MS72 to Y.Yu)the“Eastern Scholar”Fundthe“Guangxi Bagui Scholar”fund(to Y.Shen)the Major Research Plan of the Provincial Science and Technology Foundation of Guangxi(AB16380214 to Y.Shen)Foundation of Shanghai Municipal Health Commission(shslczdzk05702,to Y.Yu and Y.Sun)Municipal Education Commission-Gaofeng Clinical Medicine Grant Support(20191908,to Y.Yu)。
文摘Mitochondrial diseases are caused by variants in both mitochondrial and nuclear genomes.A nuclear gene HPDL(4-hydroxyphenylpyruvate dioxygenase-like),which encodes an intermembrane mitochondrial protein,has been recently implicated in causing a neurodegenerative disease characterized by pediatric-onset spastic movement phenotypes.Here,we report six Chinese patients with bi-allelic HPDL pathogenic variants from four unrelated families showing neuropathic symptoms of variable severity,including developmental delay/intellectual disability,spasm,and hypertonia.Seven different pathogenic variants are identified,of which five are novel.Both fibroblasts and immortalized lymphocytes derived from patients show impaired mitochondrial respiratory function,which is also observed in HPDL-knockdown(KD)He La cells.In these He La cells,overexpression of a wild-type HPDL gene can rescue the respiratory phenotype of oxygen consumption rate.In addition,a decreased activity of the oxidative phosphorylation(OXPHOS)complex II is observed in patient-derived lymphocytes and HPDL-KD He La cells,further supporting an essential role of HPDL in the mitochondrial respiratory chain.Collectively,our data expand the clinical and mutational spectra of this mitochondrial neuropathy and further delineate the possible disease mechanism involving the impairment of the OXPHOS complex II activity due to the bi-allelic inactivations of HPDL.
文摘Dear Editor,Dilated cardiomyopathy(DCM)is a common form of inherited cardiomyopathy.In the past decades,single mutations in various genes encoding sarcomeric,cytoskeletal,and channel proteins etc.have been found to be associated with DCM(Hershberger et al.,2013;McNally and Mestroni,2017).However,the mechanisms how single mutations in sarcomeric or structural genes lead to the disease remain elusive.An interesting phenomenon often seen in familial cardiomyopathy is that different single mutations on the same gene can cause either DCM or hypertrophic cardiomyopathy(HCM)(Kathiresan and Srivastava,2012),which exhibit almost opposite disease phenotypes.DCM is characterized by thinned myocardium and septum,ventricular chamber dilation,and systolic dysfunction(Jefferies and Towbin,2010;McNally and Mestroni,2017),while HCM exhibits thickened myocardium and septum,reduced ventricular chamber,and diastolic dysfunction(Richard et al.,2003).At the cellular level,HCM cardiomyocytes exhibit concentric hypertrophy characterized by assembly of myofilaments in parallel and widening of the myocytes.In contrast,DCM cardiomyocytes show eccentric hypertrophy,with assembly of the myofilaments in series and myocyte elongation(Kehat and Molkentin,2010).
