A5033564415- Genetic Neurodegenerative Diseases
- Mitochondrial Function and Pathology
- DNA Repair Mechanisms
- Neurological disorders and treatments
- Fungal and yeast genetics research
- RNA Research and Splicing
- Parkinson's Disease Mechanisms and Treatments
- CRISPR and Genetic Engineering
- Neuroinflammation and Neurodegeneration Mechanisms
- Genetic Associations and Epidemiology
- Genetics and Neurodevelopmental Disorders
- Fermentation and Sensory Analysis
- Muscle Physiology and Disorders
- Alzheimer's disease research and treatments
- Hereditary Neurological Disorders
- Autism Spectrum Disorder Research
- Signaling Pathways in Disease
- RNA and protein synthesis mechanisms
- Neurology and Historical Studies
Cardiff University
2017-2024
Massachusetts General Hospital
2021-2024
Medical Research Council
2019-2022
Universität Ulm
2021
Harvard University
2021
Objective To assess the prevalence, timing, and functional impact of psychiatric, cognitive, motor abnormalities in Huntington disease (HD) gene carriers, we analyzed retrospective clinical data from individuals with manifest HD. Methods Clinical features patients HD were for 6,316 an observational study European Huntington's Disease Network (REGISTRY) 161 sites across 17 countries. Data came history patient-completed Characteristics Questionnaire that assessed 8 symptoms: motor, apathy,...
Abstract The age at onset of motor symptoms in Huntington’s disease (HD) is driven by HTT CAG repeat length but modified other genes. In this study, we used exome sequencing 683 patients with HD extremes or phenotype relative to identify rare variants associated clinical effect. We discovered damaging coding candidate modifier genes identified previous genome-wide association studies altered severity. Variants FAN1 clustered its DNA-binding and nuclease domains were predominantly...
Many Mendelian disorders, such as Huntington’s disease (HD) and spinocerebellar ataxias, arise from expansions of CAG trinucleotide repeats. Despite the clear genetic causes, additional factors may influence rate those monogenic disorders. Notably, genome-wide association studies discovered somewhat expected modifiers, particularly mismatch repair genes involved in repeat instability, impacting age at onset HD. Strikingly, FAN1 , previously unrelated to produced strongest HD modification...
BackgroundHuntington's disease (HD) is an inherited neurodegenerative disorder caused by expanded CAG repeat in the HTT gene. It diagnosed following a standardized examination of motor control and often presents with cognitive decline psychiatric symptoms. Recent studies have detected genetic loci modifying age at onset symptoms HD, but factors influencing presentations are unknown.MethodsWe tested hypothesis that HD influenced same common variation as general population 1) constructing...
Abstract Expansions of glutamine-coding CAG trinucleotide repeats cause a number neurodegenerative diseases, including Huntington’s disease and several spinocerebellar ataxias. In general, age-at-onset the polyglutamine diseases is inversely correlated with size respective inherited expanded repeat. Expanded are also somatically unstable in certain tissues, corrected for individual HTT repeat length (i.e. residual age-at-onset), modified by instability-related DNA maintenance/repair genes as...
Abstract Huntington’s disease is caused by an expanded CAG tract in HTT . The length of the accounts for over half variance age at onset disease, and influenced other genetic factors, mostly implicating DNA maintenance machinery. We examined a single nucleotide variant, rs79727797, on chromosome 5 TCERG1 gene, previously reported to be associated with quasi-tandem repeat (QTR) hexamer exon 4 central pure repeat. developed method calling perfect imperfect repeats from exome-sequencing data,...
Targeted DNA sequencing approaches will improve how the size of short tandem repeats is measured for diagnostic tests and preclinical studies. The expansion these sequences causes dozens disorders, with longer tracts generally leading to a more severe disease. Interrupted alleles are sometimes present within can alter disease manifestation. Determining repeat mosaicism identifying interruptions in targeted datasets remains major challenge. This part because standard alignment tools...
Huntington's disease (HD) is a neurodegenerative disorder caused by dominantly inherited CAG repeat expansion in the huntingtin gene (HTT). Neuroinflammation and microglia have been implicated HD pathology, however it has unclear if mutant HTT (mHTT) expression an adverse cell-autonomous effect on microglial function, or they are only activated response to brain environment HD. To establish human cell model of we generated isogenic controls for patient-derived induced pluripotent stem cells...
SUMMARY The effects of variable, glutamine-encoding, CAA interruptions indicate that a property the uninterrupted HTT CAG repeat sequence, distinct from huntingtin’s polyglutamine segment, dictates rate at which HD develops. timing onset shows no significant association with cis -eQTLs but is influenced, sometimes in sex-specific manner, by polymorphic variation multiple DNA maintenance genes, suggesting special onset-determining propensity for length instability leads to its somatic...
Background: Huntington’s disease (HD) is caused by an expanded (>35) CAG trinucleotide repeat in huntingtin (HTT). Age-at-onset of motor symptoms inversely correlated with the size inherited repeat, which expands further brain regions due to somatic instability. Our recent genetic investigation focusing on autosomal SNPs revealed that age-at-onset also influenced variation at many loci, majority encode genes involved DNA maintenance/repair processes and Objective: We performed a...
Summary The age at onset of motor symptoms in Huntington’s disease (HD) is driven by HTT CAG repeat length but modified other genes. We used exome sequencing 683 HD patients with extremes or phenotype relative to identify rare variants associated clinical effect. identified damaging coding candidate modifier genes from prior genome-wide association studies altered severity. Variants FAN1 clustered its DNA-binding and nuclease domains were predominantly earlier HD. Nuclease activities these...
Abstract Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by expanded CAG repeat in the HTT gene. It diagnosed following a standardized exam of motor control and often presents with cognitive decline psychiatric symptoms. Recent studies have detected genetic loci modifying age at onset symptoms HD, but factors influencing presentations are unknown. We tested hypothesis that HD influenced same common variation as general population constructing polygenic risk scores...
Abstract Objective To assess the prevalence, timing and functional impact of psychiatric, cognitive motor abnormalities in Huntington’s disease (HD) gene carriers, we analysed retrospective clinical data from individuals with manifest HD. Methods Clinical features HD patients were for 6316 European REGISTRY study 161 sites across 17 countries. Data came history patient-completed Characteristics Questionnaire that assessed eight symptoms: motor, cognitive, apathy, depression,...
Abstract Genome-wide association studies (GWAS) of Huntington’s disease (HD) have identified six DNA maintenance gene loci (among others) as modifiers and implicated a two step-mechanism pathogenesis: somatic instability the causative HTT CAG repeat with subsequent triggering neuronal damage. The largest been limited to HD individuals rater-estimated age at motor onset. To capitalize on wealth phenotypic data in several large natural history studies, we performed algorithmic prediction using...
Abstract Background Huntington’s disease is caused by an expanded CAG tract in HTT . The length of the accounts for over half variance age at onset disease, and influenced other genetic factors, mostly implicating DNA maintenance machinery. We examined a single nucleotide variant, rs79727797, on chromosome 5 TCERG1 gene, previously reported to be associated with quasi-tandem repeat (QTR) hexamer exon 4 central pure repeat. Methods developed novel method calling perfect imperfect repeats from...
Abstract The Apolipoprotein-E4 allele (APOE) is the strongest genetic risk factor for sporadic Alzheimer’s disease but its role in pathogenesis incompletely understood. APOE gene encodes Apolipoprotein E (ApoE). Astrocytes are main source of ApoE central nervous system (CNS) and essential homeostasis health disease. In response to CNS insult, a coordinated multicellular inflammatory triggered causing reactive astrogliosis with changes astrocytic expression, cellular structure function. Human...
<h3></h3> Huntington’s Disease is a life-shortening neurodegenerative condition caused by CAG repeat expansion in exon 1 of the <i>HTT</i> gene. The age at onset involuntary motor symptoms inversely correlated with length but there considerable variation between patients. A recent genome-wide association study has identified DNA repair processes as significant modifiers which start. Our work aims to investigate this link further using exome sequencing stratified HD population particularly...
<h3>Background</h3> CAG repeat expansions in exon 1 of the Huntingtin gene (HTT) cause Huntington's disease (HD). Longer tracts correlate inversely with onset, but there remains considerable variation between individuals at same size (˜50%). A recent GWAS highlighted DNA repair genes as modifiers HD onset. To improve our understanding effects we used whole-exome sequencing (WES) an extreme onset cohort to investigate rare coding potentially large effect. <h3>Aims</h3> Stratify REGISTRY–HD...
<h3>Background</h3> Age at motor onset and disease progression in HD have a genetic contribution. Psychiatric symptoms are more frequent compared with the general population there is some evidence that these heritable. <h3>Aims</h3> To test for shared liability between neuropsychiatric disorders presence of psychiatric (psychosis, irritability, depression, apathy, violence/aggression, obsessive behaviour, cognitive dysfunction) REGISTRY cohort. <h3>Methods/techniques</h3> The phenotypes was...
<h3>Background</h3> Huntington's disease (HD) is caused by an expanded CAG repeat in the <i>HTT</i> gene on chromosome 4 with longer repeats being associated earlier onset disease. However, recent genetic studies have shown that other genes also a significant effect and progression of HD. Many these 'modifier' are involved DNA repair thought to influence HD affecting stability striatal neurons. <h3>Aims</h3> To identify coding variants significantly or later <h3>Methods</h3> We stratified...
<h3>Background</h3> Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG repeat in huntingtin gene, HTT. The length inversely correlated with age at motor onset but other factors influence including genetic variation elsewhere genome. Recent genome-wide association studies (GWAS) have identified variants or near DNA repair genes as modifiers onset. We hypothesise that processes trigger post-mitotic medium spiny neurons (MSNs), cells...