The polymorphic CAG repeats in the IT15 gene in Chinese normal and Huntington’s dis-ease(HD)chromosomes were determined by using nested PCR and denaturing polyacry-lamide gel electrophoretic autoradiography as well a...The polymorphic CAG repeats in the IT15 gene in Chinese normal and Huntington’s dis-ease(HD)chromosomes were determined by using nested PCR and denaturing polyacry-lamide gel electrophoretic autoradiography as well as direct sequencing analysis.A total of40 normal individuals and 122 members of 13 unrelated HD families originating from Shang-hai,Jiangsu,Zhejiang,Anhui,Shandong,Guangdong and Henan,respectively,were in-volved in this study.The results showed that the(CAG)n repeat numbers in 270 normal al-leles ranged from 13 to 26 but most in 16;while in 54 HD alleles,the CAG repeats from 40to 94,with an unstable inheritance of expanded repeats in some families.There was no over-lap between the normal and affected alleles.Additionally,the presymptomatic diagnosis in103 family members at risk for HD disclosed that 35 individuals had HD alleles,which were-in accordance with the pedigree analysis and clinical investigation.All these results indicatedthat the dynamic mutation in IT15 gene was responsible for the genetic defect in the ChineseHD patients and that a correlation existed between the numbers of(CAG)n repeat and theonset age of the disease.All-of these provide valuable data for HD molecular diagnosis,ge-netic counselling and genetic health.展开更多
We report brain imaging and genetic diagnosis in a family from Wuhan, China, with a history of Huntington＇s disease. Among 17 family members across three generations, four patients （Ⅱ2, Ⅱ6, Ⅲ5, and Ⅲ9） show typ...We report brain imaging and genetic diagnosis in a family from Wuhan, China, with a history of Huntington＇s disease. Among 17 family members across three generations, four patients （Ⅱ2, Ⅱ6, Ⅲ5, and Ⅲ9） show typical Huntington＇s disease, involuntary dance-like movements. Magnetic resonance imaging found lateral ventricular atrophy in three members （Ⅱ2, Ⅱ6, and Ⅲ5）. Moreover, genetic analysis identified abnormally amplified CAG sequence repeats （〉 40） in two members （Ⅲ5 and Ⅲ9）. Among borderline cases, with clinical symptoms and brain imaging features of Huntington＇s disease, two cases were identified （Ⅱ2 and Ⅱ6）, but shown by mutation analysis for CAG expansions in the important transcript 15 gene, to be non-Huntington＇s disease. Our findings suggest that clinical diagnosis of Huntington＇s disease requires a combination of clinical symptoms, radiological changes, and genetic diagnosis.展开更多
Huntington's disease(HD)is caused by a CAG repeat expansion in the huntingtin(HTT)gene.Knock-in mice carrying a CAG repeat-expanded Htt will develop HD phenotypes.Previous studies suggested dysregulated molecular ...Huntington's disease(HD)is caused by a CAG repeat expansion in the huntingtin(HTT)gene.Knock-in mice carrying a CAG repeat-expanded Htt will develop HD phenotypes.Previous studies suggested dysregulated molecular networks in a CAG length genotype-and the age-dependent manner in brain tissues from knock-in mice carrying expanded Htt CAG repeats.Furthermore,a large-scale phenome analysis defined a behavioral signature for HD genotype in knock-in mice carrying expanded Htt CAG repeats.However,an integrated analysis correlating phenotype features with genotypes(CAG repeat expansions)was not conducted previously.In this study,we revealed the landscape of the behavioral features and gene expression correlations based on 445 mRNA samples and 445 microRNA samples,together with behavioral features(396 PhenoCube behaviors and 111 NeuroCube behaviors)in Htt CAG-knock-in mice.We identified 37 behavioral features that were significantly associated with CAG repeat length including the number of steps and hind limb stand duration.The behavioral features were associated with several gene coexpression groups involved in neuronal dysfunctions,which were also supported by the single-cell RNA sequencing data in the striatum and the spatial gene expression in the brain.We also identified 15 chemicals with significant responses for genes with enriched behavioral features,most of them are agonist or antagonist for dopamine receptors and serotonin receptors used for neurology/psychiatry.Our study provides further evidence that abnormal neuronal signal transduction in the striatum plays an important role in causing HD-related phenotypic behaviors and provided rich information for the further pharmacotherapeutic intervention possibility for HD.展开更多
基金the High Technology Research Development Programme of China
文摘The polymorphic CAG repeats in the IT15 gene in Chinese normal and Huntington’s dis-ease(HD)chromosomes were determined by using nested PCR and denaturing polyacry-lamide gel electrophoretic autoradiography as well as direct sequencing analysis.A total of40 normal individuals and 122 members of 13 unrelated HD families originating from Shang-hai,Jiangsu,Zhejiang,Anhui,Shandong,Guangdong and Henan,respectively,were in-volved in this study.The results showed that the(CAG)n repeat numbers in 270 normal al-leles ranged from 13 to 26 but most in 16;while in 54 HD alleles,the CAG repeats from 40to 94,with an unstable inheritance of expanded repeats in some families.There was no over-lap between the normal and affected alleles.Additionally,the presymptomatic diagnosis in103 family members at risk for HD disclosed that 35 individuals had HD alleles,which were-in accordance with the pedigree analysis and clinical investigation.All these results indicatedthat the dynamic mutation in IT15 gene was responsible for the genetic defect in the ChineseHD patients and that a correlation existed between the numbers of(CAG)n repeat and theonset age of the disease.All-of these provide valuable data for HD molecular diagnosis,ge-netic counselling and genetic health.
基金supported by the Fundamental Research Funds for the Central Universities,No.20100141110017,20103030201000217 and 201130302020008
文摘We report brain imaging and genetic diagnosis in a family from Wuhan, China, with a history of Huntington＇s disease. Among 17 family members across three generations, four patients （Ⅱ2, Ⅱ6, Ⅲ5, and Ⅲ9） show typical Huntington＇s disease, involuntary dance-like movements. Magnetic resonance imaging found lateral ventricular atrophy in three members （Ⅱ2, Ⅱ6, and Ⅲ5）. Moreover, genetic analysis identified abnormally amplified CAG sequence repeats （〉 40） in two members （Ⅲ5 and Ⅲ9）. Among borderline cases, with clinical symptoms and brain imaging features of Huntington＇s disease, two cases were identified （Ⅱ2 and Ⅱ6）, but shown by mutation analysis for CAG expansions in the important transcript 15 gene, to be non-Huntington＇s disease. Our findings suggest that clinical diagnosis of Huntington＇s disease requires a combination of clinical symptoms, radiological changes, and genetic diagnosis.
基金This research was supported by the National Natural Science Foundation of China(No.81970839 and 81670895 to L.H.)the Department of Science and Technology of Sichuan Province,China(No.2021YFS0033 to L.H).
文摘Huntington's disease(HD)is caused by a CAG repeat expansion in the huntingtin(HTT)gene.Knock-in mice carrying a CAG repeat-expanded Htt will develop HD phenotypes.Previous studies suggested dysregulated molecular networks in a CAG length genotype-and the age-dependent manner in brain tissues from knock-in mice carrying expanded Htt CAG repeats.Furthermore,a large-scale phenome analysis defined a behavioral signature for HD genotype in knock-in mice carrying expanded Htt CAG repeats.However,an integrated analysis correlating phenotype features with genotypes(CAG repeat expansions)was not conducted previously.In this study,we revealed the landscape of the behavioral features and gene expression correlations based on 445 mRNA samples and 445 microRNA samples,together with behavioral features(396 PhenoCube behaviors and 111 NeuroCube behaviors)in Htt CAG-knock-in mice.We identified 37 behavioral features that were significantly associated with CAG repeat length including the number of steps and hind limb stand duration.The behavioral features were associated with several gene coexpression groups involved in neuronal dysfunctions,which were also supported by the single-cell RNA sequencing data in the striatum and the spatial gene expression in the brain.We also identified 15 chemicals with significant responses for genes with enriched behavioral features,most of them are agonist or antagonist for dopamine receptors and serotonin receptors used for neurology/psychiatry.Our study provides further evidence that abnormal neuronal signal transduction in the striatum plays an important role in causing HD-related phenotypic behaviors and provided rich information for the further pharmacotherapeutic intervention possibility for HD.
