Retinitis pigmentosa(RP),a major cause of inherited blindness worldwide,is highly heterogeneous.This study aimed to identify mutations in a Chinese cohort of sporadic probands with presumptive RP.Whole exome sequencin...Retinitis pigmentosa(RP),a major cause of inherited blindness worldwide,is highly heterogeneous.This study aimed to identify mutations in a Chinese cohort of sporadic probands with presumptive RP.Whole exome sequencing represents a considerable advancement in the identification of mutations associated with Mendelian diseases,such as RP.In this study,whole exome sequencing analysis was performed in a Chinese cohort of 95 sporadic probands who were initially diagnosed with RP,in order to identify disease mutations.All detected variations were confirmed by direct Sanger sequencing,and potential pathogenicity was assessed by predictions of the mutations’functions.The overall mutation rate of presumptive RP genes for this cohort was 30.5%(n=29 of 95 probands).Forty-four mutations were identified in 19 RP genes,among which 40 mutations were novel.Eleven probands carried mutations in autosomal dominant genes(38.0%),16 probands carried mutations in autosomal recessive genes(55.2%),and 2 probands carried mutations in X-linked genes(6.9%).Twenty-eight mutations in 18 genes linked to other retinal diseases in 23 probands were also identified.Overall,mutations were detected in 52 probands(54.7%).The recurrent and novel mutations reported here will expand potential understanding of the pathogenesis of RP and other retinal diseases.展开更多
ObjectiveTo seek potential pathogenic variants in sarcomere genes in arrhythmogenic cardiomyopathy(ACM)and describe the characteristics.Methods and Results We performed targeted sequencing of 14sarcomere genes in 118 ...ObjectiveTo seek potential pathogenic variants in sarcomere genes in arrhythmogenic cardiomyopathy(ACM)and describe the characteristics.Methods and Results We performed targeted sequencing of 14sarcomere genes in 118 cases with the clinical diagnosis of ARVC and Sanger sequencing of the specific variants in family members of the probands.展开更多
Essential tremor(ET)is a common neurological disease that is characterized by 4–12 Hz kinetic tremors of the upper limbs and high genetic heterogeneity.Although numerous candidate genes and loci have been reported,th...Essential tremor(ET)is a common neurological disease that is characterized by 4–12 Hz kinetic tremors of the upper limbs and high genetic heterogeneity.Although numerous candidate genes and loci have been reported,the etiology of ET remains unclear.A novel ET-related gene was initially identified in a five-generation family via whole-exome sequencing,and other variants were identified in 772 familial ET probands and 640 sporadic individuals via whole-genome sequencing.Among 71(9.18%)Chinese families and 47(7.34%)sporadic individuals with ET,we identified 15 types of protein-altering variants in solute carrier family 38 member 6(SLC38A6),which encodes sodium-coupled neutral amino acid transporter 6(SNAT6)and is inherited in an autosomal dominant pattern.Over-expression of mutant SNAT6 for the three most common human mutations(p.Y108F,p.M281T and p.G318S)significantly impaired L-arginine(L-Arg)uptake in HeLa cells.The homozygous Slc38a6 deletion mice(Slc38a6-/-)exhibited reduced L-Arg uptake in their cerebellar neurons,tremor,and cerebellar pathology.Slice electrophysiology revealed reduced neuronal Purkinje cell(PC)excitability and elevated inhibitory synaptic transmission in Slc38a6^(-/-)mice,in line with elevated“hairy”basket coverage around the PC soma.Furthermore,heterozygous Slc38a6 deletion(Slc38a6^(+/-))and PC-specific Slc38a6 deletion(Slc38a6^(PC-/-))mice also displayed tremor and PC abnormalities similar to those found in Slc38a6^(-/-)mice.These PCs displayed mitochondrial abnormalities and elevated ferroptosis markers(ACSL4,TFRC and Fe ions).In conclusion,we identified variants in SLC38A6 that contribute~8.35%to ET,generated mouse models displaying tremor,and delineated cerebellar cellular abnormalities and potential mechanisms underlying ET etiology.展开更多
基金supported by the National Key Scientific Research Program(No.2016YFC0905200,toZY)the National Natural Science Foundation of China(No.81170883,81790643 and 81430008(to ZY),81300802 and 81670895(to LH),81271048(to JY),81570848 and 81100693(to CQ))+1 种基金by the Department of Science and Technology of Sichuan Province,China(No.2014SZ0169,2015SZ0052(to ZY),2015JQO057(to LH),2016HH0072(to LH),2017JQ0024(to LH),2015SZ0060(to YL),2013JY0195(to LH),2015SZ0060(to YL),2014FZ0124(to DYL)and 2015JZ0004(to CQ))High-level Talents Program of UESTC Y03001023601021016(to LH).
文摘Retinitis pigmentosa(RP),a major cause of inherited blindness worldwide,is highly heterogeneous.This study aimed to identify mutations in a Chinese cohort of sporadic probands with presumptive RP.Whole exome sequencing represents a considerable advancement in the identification of mutations associated with Mendelian diseases,such as RP.In this study,whole exome sequencing analysis was performed in a Chinese cohort of 95 sporadic probands who were initially diagnosed with RP,in order to identify disease mutations.All detected variations were confirmed by direct Sanger sequencing,and potential pathogenicity was assessed by predictions of the mutations’functions.The overall mutation rate of presumptive RP genes for this cohort was 30.5%(n=29 of 95 probands).Forty-four mutations were identified in 19 RP genes,among which 40 mutations were novel.Eleven probands carried mutations in autosomal dominant genes(38.0%),16 probands carried mutations in autosomal recessive genes(55.2%),and 2 probands carried mutations in X-linked genes(6.9%).Twenty-eight mutations in 18 genes linked to other retinal diseases in 23 probands were also identified.Overall,mutations were detected in 52 probands(54.7%).The recurrent and novel mutations reported here will expand potential understanding of the pathogenesis of RP and other retinal diseases.
文摘ObjectiveTo seek potential pathogenic variants in sarcomere genes in arrhythmogenic cardiomyopathy(ACM)and describe the characteristics.Methods and Results We performed targeted sequencing of 14sarcomere genes in 118 cases with the clinical diagnosis of ARVC and Sanger sequencing of the specific variants in family members of the probands.
基金supported by the Natural Science Foundation of China(Grants U20A20355 and 32270663)the China Postdoctoral Science Foundation(Grant 2024M762007 and Postdoctoral Fellowship Program Grade B GZB20240453)the Shanghai Municipal Science and Technology Major Project(2018SHZDZX05).
文摘Essential tremor(ET)is a common neurological disease that is characterized by 4–12 Hz kinetic tremors of the upper limbs and high genetic heterogeneity.Although numerous candidate genes and loci have been reported,the etiology of ET remains unclear.A novel ET-related gene was initially identified in a five-generation family via whole-exome sequencing,and other variants were identified in 772 familial ET probands and 640 sporadic individuals via whole-genome sequencing.Among 71(9.18%)Chinese families and 47(7.34%)sporadic individuals with ET,we identified 15 types of protein-altering variants in solute carrier family 38 member 6(SLC38A6),which encodes sodium-coupled neutral amino acid transporter 6(SNAT6)and is inherited in an autosomal dominant pattern.Over-expression of mutant SNAT6 for the three most common human mutations(p.Y108F,p.M281T and p.G318S)significantly impaired L-arginine(L-Arg)uptake in HeLa cells.The homozygous Slc38a6 deletion mice(Slc38a6-/-)exhibited reduced L-Arg uptake in their cerebellar neurons,tremor,and cerebellar pathology.Slice electrophysiology revealed reduced neuronal Purkinje cell(PC)excitability and elevated inhibitory synaptic transmission in Slc38a6^(-/-)mice,in line with elevated“hairy”basket coverage around the PC soma.Furthermore,heterozygous Slc38a6 deletion(Slc38a6^(+/-))and PC-specific Slc38a6 deletion(Slc38a6^(PC-/-))mice also displayed tremor and PC abnormalities similar to those found in Slc38a6^(-/-)mice.These PCs displayed mitochondrial abnormalities and elevated ferroptosis markers(ACSL4,TFRC and Fe ions).In conclusion,we identified variants in SLC38A6 that contribute~8.35%to ET,generated mouse models displaying tremor,and delineated cerebellar cellular abnormalities and potential mechanisms underlying ET etiology.
