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"neurogenetics"
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Analysis of morphine responses in mice reveals a QTL on Chromosome 7 version 1; peer review: 2 approved
In this study we identified a quantitative trait locus (QTL) on mouse Chromosome 7 associated with locomotor activity and rearing post morphine treatment. This QTL was revealed after correcting for the effects of another QTL peak on Chromosome 10 using composite interval mapping. The positional candidate genes are
Syt9 and
Ppfibp2. Several other genes within the interval are linked to neural processes, locomotor activity, and the defensive response to harmful stimuli.
Journal Article
Hereditary Spastic Paraplegia: An Update
Hereditary spastic paraplegia (HSP) is a rare neurodegenerative disorder with the predominant clinical manifestation of spasticity in the lower extremities. HSP is categorised based on inheritance, the phenotypic characters, and the mode of molecular pathophysiology, with frequent degeneration in the axon of cervical and thoracic spinal cord’s lateral region, comprising the corticospinal routes. The prevalence ranges from 0.1 to 9.6 subjects per 100,000 reported around the globe. Though modern medical interventions help recognize and manage the disorder, the symptomatic measures remain below satisfaction. The present review assimilates the available data on HSP and lists down the chromosomes involved in its pathophysiology and the mutations observed in the respective genes on the chromosomes. It also sheds light on the treatment available along with the oral/intrathecal medications, physical therapies, and surgical interventions. Finally, we have discussed the related diagnostic techniques as well as the linked pharmacogenomics studies under future perspectives.
Journal Article
Environmental enrichment, new neurons and the neurobiology of individuality
‘Enriched environments’ are a key experimental paradigm to decipher how interactions between genes and environment change the structure and function of the brain across the lifespan of an animal. The regulation of adult hippocampal neurogenesis by environmental enrichment is a prime example of this complex interaction. As each animal in an enriched environment will have a slightly different set of experiences that results in downstream differences between individuals, enrichment can be considered not only as an external source of rich stimuli but also to provide the room for individual behaviour that shapes individual patterns of brain plasticity and thus function.Environmental enrichment is a classical experimental paradigm for the study of the interaction between genes and the environment. In this Opinion, Kempermann discusses how this paradigm can be further developed in order to capture the essence of interindividual differences in brain function.
Journal Article
Dissecting the genetic basis of focal cortical dysplasia: a large cohort study
Genetic malformations of cortical development (MCDs), such as mild MCDs (mMCD), focal cortical dysplasia (FCD), and hemimegalencephaly (HME), are major causes of severe pediatric refractory epilepsies subjected to neurosurgery. FCD2 are characterized by neuropathological hallmarks that include enlarged dysmorphic neurons (DNs) and balloon cells (BCs). Here, we provide a comprehensive assessment of the contribution of germline and somatic variants in a large cohort of surgical MCD cases. We enrolled in a monocentric study 80 children with drug-resistant epilepsy and a postsurgical neuropathological diagnosis of mMCD, FCD1, FCD2, or HME. We performed targeted gene sequencing ( ≥ 2000X read depth) on matched blood–brain samples to search for low-allele frequency variants in mTOR pathway and FCD genes. We were able to elucidate 29% of mMCD/FCD1 patients and 63% of FCD2/HME patients. Somatic loss-of-function variants in the N-glycosylation pathway-associated SLC35A2 gene were found in mMCD/FCD1 cases. Somatic gain-of-function variants in MTOR and its activators (AKT3, PIK3CA, RHEB), as well as germline, somatic and two-hit loss-of-function variants in its repressors (DEPDC5, TSC1, TSC2) were found exclusively in FCD2/HME cases. We show that panel-negative FCD2 cases display strong pS6-immunostaining, stressing that all FCD2 are mTORopathies. Analysis of microdissected cells demonstrated that DNs and BCs carry the pathogenic variants. We further observed a correlation between the density of pathological cells and the variant-detection likelihood. Single-cell microdissection followed by sequencing of enriched pools of DNs unveiled a somatic second-hit loss-of-heterozygosity in a DEPDC5 germline case. In conclusion, this study indicates that mMCD/FCD1 and FCD2/HME are two distinct genetic entities: while all FCD2/HME are mosaic mTORopathies, mMCD/FCD1 are not caused by mTOR-pathway-hyperactivating variants, and ~ 30% of the cases are related to glycosylation defects. We provide a framework for efficient genetic testing in FCD/HME, linking neuropathology to genetic findings and emphasizing the usefulness of molecular evaluation in the pediatric epileptic neurosurgical population.
Journal Article
Clinical features of NOTCH2NLC-related neuronal intranuclear inclusion disease
BackgroundAbnormal expanded GGC repeats within the NOTCH2HLC gene has been confirmed as the genetic mechanism for most Asian patients with neuronal intranuclear inclusion disease (NIID). This cross-sectional observational study aimed to characterise the clinical features of NOTCH2NLC-related NIID in China.MethodsPatients with NOTCH2NLC-related NIID underwent an evaluation of clinical symptoms, a neuropsychological assessment, electrophysiological examination, MRI and skin biopsy.ResultsIn the 247 patients with NOTCH2NLC-related NIID, 149 cases were sporadic, while 98 had a positive family history. The most common manifestations were paroxysmal symptoms (66.8%), autonomic dysfunction (64.0%), movement disorders (50.2%), cognitive impairment (49.4%) and muscle weakness (30.8%). Based on the initial presentation and main symptomology, NIID was divided into four subgroups: dementia dominant (n=94), movement disorder dominant (n=63), paroxysmal symptom dominant (n=61) and muscle weakness dominant (n=29). Clinical (42.7%) and subclinical (49.1%) peripheral neuropathies were common in all types. Typical diffusion-weighted imaging subcortical lace signs were more frequent in patients with dementia (93.9%) and paroxysmal symptoms types (94.9%) than in those with muscle weakness (50.0%) and movement disorders types (86.4%). GGC repeat sizes were negatively correlated with age of onset (r=−0.196, p<0.05), and in the muscle weakness-dominant type (median 155.00), the number of repeats was much higher than in the other three groups (p<0.05). In NIID pedigrees, significant genetic anticipation was observed (p<0.05) without repeat instability (p=0.454) during transmission.ConclusionsNIID is not rare; however, it is usually misdiagnosed as other diseases. Our results help to extend the known clinical spectrum of NOTCH2NLC-related NIID.
Journal Article
A putative role for genome-wide epigenetic regulatory mechanisms in Huntington's disease: A computational assessment version 1; peer review: 1 approved, 1 not approved
Background: Huntington's Disease (HD) is an incurable disease of the adult brain. Massive changes in gene expression are a prominent feature. Epigenetic effects have been reported to be implicated in HD, but the role of chromatin is not well understood. We tested if the chromatin state of dysregulated genes in HD is affected at a genome-wide scale and examined how epigenetic processes are associated with CpG-island-mediated gene expression.
Methods: Our general approach incorporates computational and functional analysis of public data before embarking on expensive wet-lab experiments. We compared the location in the genome of the genes that were deregulated in HD human brain, obtained from public gene expression data, to the location of particular chromatin marks in reference tissues using data from the ENCODE project.
Results: We found that differentially expressed genes were enriched in the active chromatin state, but not enriched in the silent state. In the caudate nucleus, the most highly affected brain region in HD, genes in the active state were associated with transcription, cell cycle, protein transport and modification, RNA splicing, histone post-translational modifications and RNA processing. Genes in the repressed state were linked with developmental processes and responses related to zinc and cadmium stimulus. We confirmed that genes within CpG-islands are enriched among HD dysregulated genes in human and mouse in HD. Epigenetic processes were associated more with genes that overlap with CpG-islands than genes that do not.
Conclusion: Our results suggest that massive transcriptional dysregulation in HD is not matched by large-scale relocation of gene activity, i.e. inactive chromatin regions are altered into actively expressed chromatin regions and vice versa. We expect that changes in epigenetic chromatin state might occur at the level of single genes (e.g. promoters, gene body) and scattered genomic sites (e.g. CTCF sites, enhancer regions) instead of large-scale genomic regions.
Journal Article
Long-read sequencing identified repeat expansions in the 5′UTR of the NOTCH2NLC gene from Chinese patients with neuronal intranuclear inclusion disease
BackgroundNeuronal intranuclear inclusion disease (NIID) is a heterogenous neurodegenerative disorder named after its pathological features. It has long been considered a disease of genetic origin. Recently, the GGC repeated expansion in the 5′-untranslated region (5′UTR) of the NOTCH2NLC gene has been found in adult-onset NIID in Japanese individuals. This study was aimed to investigate the causative mutations of NIID in Chinese patients.MethodsFifteen patients with NIID were identified from five academic neurological centres. Biopsied skin samples were analysed by histological staining, immunostaining and electron microscopic observation. Whole-genome sequencing (WGS) and long-read sequencing (LRS) were initially performed in three patients with NIID. Repeat-primed PCR was conducted to confirm the genetic variations in the three patients and the other 12 cases.ResultsOur patients included 14 adult-onset patients and 1 juvenile-onset patient characterised by degeneration of multiple nervous systems. All patients were identified with intranuclear inclusions in the nuclei of fibroblasts, fat cells and ductal epithelial cells of sweat glands. The WGS failed to find any likely pathogenic variations for NIID. The LRS successfully identified that three patients with adult-onset NIID showed abnormalities of GGC expansion in 5′UTR of the NOTCH2NLC gene. The GGC repeated expansion was further confirmed by repeat-primed PCR in seven familial cases and eight sporadic cases.ConclusionOur findings provided evidence that confirmed the GGC repeated expansion in the 5′UTR of the NOTCH2NLC gene is associated with the pathogenesis of NIID. Additionally, the GGC expansion was not only responsible for adult-onset patients, but also responsible for juvenile-onset patients.
Journal Article