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1.
Neuropathol Appl Neurobiol ; 49(1): e12872, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36542090

RESUMEN

AIMS: Epigenetic clocks are widely applied as surrogates for biological age in different tissues and/or diseases, including several neurodegenerative diseases. Despite white matter (WM) changes often being observed in neurodegenerative diseases, no study has investigated epigenetic ageing in white matter. METHODS: We analysed the performances of two DNA methylation-based clocks, DNAmClockMulti and DNAmClockCortical , in post-mortem WM tissue from multiple subcortical regions and the cerebellum, and in oligodendrocyte-enriched nuclei. We also examined epigenetic ageing in control and multiple system atrophy (MSA) (WM and mixed WM and grey matter), as MSA is a neurodegenerative disease comprising pronounced WM changes and α-synuclein aggregates in oligodendrocytes. RESULTS: Estimated DNA methylation (DNAm) ages showed strong correlations with chronological ages, even in WM (e.g., DNAmClockCortical , r = [0.80-0.97], p < 0.05). However, performances and DNAm age estimates differed between clocks and brain regions. DNAmClockMulti significantly underestimated ages in all cohorts except in the MSA prefrontal cortex mixed tissue, whereas DNAmClockCortical tended towards age overestimations. Pronounced age overestimations in the oligodendrocyte-enriched cohorts (e.g., oligodendrocyte-enriched nuclei, p = 6.1 × 10-5 ) suggested that this cell type ages faster. Indeed, significant positive correlations were observed between estimated oligodendrocyte proportions and DNAm age acceleration estimated by DNAmClockCortical (r > 0.31, p < 0.05), and similar trends were obtained with DNAmClockMulti . Although increased age acceleration was observed in MSA compared with controls, no significant differences were detected upon adjustment for possible confounders (e.g., cell-type proportions). CONCLUSIONS: Our findings show that oligodendrocyte proportions positively influence epigenetic age acceleration across brain regions and highlight the need to further investigate this in ageing and neurodegeneration.


Asunto(s)
Atrofia de Múltiples Sistemas , Humanos , Atrofia de Múltiples Sistemas/metabolismo , Encéfalo/metabolismo , Sustancia Gris/metabolismo , Oligodendroglía/metabolismo , Metilación de ADN , Epigénesis Genética
2.
Acta Neuropathol ; 146(1): 77-95, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37149835

RESUMEN

Frontotemporal lobar degeneration (FTLD) is an umbrella term describing the neuropathology of a clinically, genetically and pathologically heterogeneous group of diseases, including frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). Among the major FTLD pathological subgroups, FTLD with TDP-43 positive inclusions (FTLD-TDP) and FTLD with tau-positive inclusions (FTLD-tau) are the most common, representing about 90% of the cases. Although alterations in DNA methylation have been consistently associated with neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, little is known for FTLD and its heterogeneous subgroups and subtypes. The main goal of this study was to investigate DNA methylation variation in FTLD-TDP and FTLD-tau. We used frontal cortex genome-wide DNA methylation profiles from three FTLD cohorts (142 FTLD cases and 92 controls), generated using the Illumina 450K or EPIC microarrays. We performed epigenome-wide association studies (EWAS) for each cohort followed by meta-analysis to identify shared differentially methylated loci across FTLD subgroups/subtypes. In addition, we used weighted gene correlation network analysis to identify co-methylation signatures associated with FTLD and other disease-related traits. Wherever possible, we also incorporated relevant gene/protein expression data. After accounting for a conservative Bonferroni multiple testing correction, the EWAS meta-analysis revealed two differentially methylated loci in FTLD, one annotated to OTUD4 (5'UTR-shore) and the other to NFATC1 (gene body-island). Of these loci, OTUD4 showed consistent upregulation of mRNA and protein expression in FTLD. In addition, in the three independent co-methylation networks, OTUD4-containing modules were enriched for EWAS meta-analysis top loci and were strongly associated with the FTLD status. These co-methylation modules were enriched for genes implicated in the ubiquitin system, RNA/stress granule formation and glutamatergic synaptic signalling. Altogether, our findings identified novel FTLD-associated loci, and support a role for DNA methylation as a mechanism involved in the dysregulation of biological processes relevant to FTLD, highlighting novel potential avenues for therapeutic development.


Asunto(s)
Demencia Frontotemporal , Degeneración Lobar Frontotemporal , Enfermedad de Pick , Humanos , Demencia Frontotemporal/patología , Degeneración Lobar Frontotemporal/patología , Encéfalo/patología , Enfermedad de Pick/patología , ADN , Proteínas tau/metabolismo , Proteasas Ubiquitina-Específicas/metabolismo
3.
Cerebellum ; 22(1): 37-45, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35034258

RESUMEN

Untranslated regions are involved in the regulation of transcriptional and post-transcriptional processes. Characterization of these regions remains poorly explored for ATXN3, the causative gene of Machado-Joseph disease (MJD). Although a few genetic modifiers have been identified for MJD age at onset (AO), they only explain a small fraction of the AO variance. Our aim was to analyse variation at the 3'UTR of ATXN3 in MJD patients, analyse its impact on AO and attempt to build haplotypes that might discriminate between normal and expanded alleles.After assessing ATXN3 3'UTR variants in molecularly confirmed MJD patients, an in silico analysis was conducted to predict their functional impact (e.g. their effect on miRNA-binding sites). Alleles in cis with the expanded (CAG)n were inferred from family data, and haplotypes were built. The effect of the alternative alleles on the AO and on SARA and NESSCA ataxia scales was tested.Nine variants, all previously described, were found. For eight variants, in silico analyses predicted (a) deleterious effects (rs10151135; rs55966267); (b) changes on miRNA-binding sites (rs11628764; rs55966267; rs709930) and (c) alterations of RNA-binding protein (RBP)-binding sites (rs1055996; rs910369; rs709930; rs10151135; rs3092822; rs7158733). Patients harbouring the alternative allele at rs10151135 had significantly higher SARA Axial subscores (p = 0.023), comparatively with those homozygous for the reference allele. Ten different haplotypes were obtained, one of which was exclusively found in cis with the expanded and four with the normal allele. These findings, which are relevant for the design of allele-specific therapies, warrant further investigation in independent MJD cohorts.


Asunto(s)
Enfermedad de Machado-Joseph , MicroARNs , Humanos , Enfermedad de Machado-Joseph/genética , Enfermedad de Machado-Joseph/metabolismo , Ataxina-3/genética , Regiones no Traducidas 3'/genética , MicroARNs/genética , Variación Genética , Proteínas Represoras/genética
4.
Alzheimers Dement ; 19(12): 5905-5921, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37606627

RESUMEN

Genetics and omics studies of Alzheimer's disease and other dementia subtypes enhance our understanding of underlying mechanisms and pathways that can be targeted. We identified key remaining challenges: First, can we enhance genetic studies to address missing heritability? Can we identify reproducible omics signatures that differentiate between dementia subtypes? Can high-dimensional omics data identify improved biomarkers? How can genetics inform our understanding of causal status of dementia risk factors? And which biological processes are altered by dementia-related genetic variation? Artificial intelligence (AI) and machine learning approaches give us powerful new tools in helping us to tackle these challenges, and we review possible solutions and examples of best practice. However, their limitations also need to be considered, as well as the need for coordinated multidisciplinary research and diverse deeply phenotyped cohorts. Ultimately AI approaches improve our ability to interrogate genetics and omics data for precision dementia medicine. HIGHLIGHTS: We have identified five key challenges in dementia genetics and omics studies. AI can enable detection of undiscovered patterns in dementia genetics and omics data. Enhanced and more diverse genetics and omics datasets are still needed. Multidisciplinary collaborative efforts using AI can boost dementia research.


Asunto(s)
Enfermedad de Alzheimer , Inteligencia Artificial , Humanos , Aprendizaje Automático , Enfermedad de Alzheimer/genética , Fenotipo , Medicina de Precisión
5.
Neurobiol Dis ; 162: 105578, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34871736

RESUMEN

Machado-Joseph disease (MJD/SCA3) is a neurodegenerative polyglutamine disorder exhibiting a wide spectrum of phenotypes. The abnormal size of the (CAG)n at ATXN3 explains ~55% of the age at onset variance, suggesting the involvement of other factors, namely genetic modifiers, whose identification remains limited. Our aim was to find novel genetic modifiers, analyse their epistatic effects and identify disease-modifying pathways contributing to MJD variable expressivity. We performed whole-exome sequencing in a discovery sample of four age at onset concordant and four discordant first-degree relative pairs of Azorean patients, to identify candidate variants which genotypes differed for each discordant pair but were shared in each concordant pair. Variants identified by this approach were then tested in an independent multi-origin cohort of 282 MJD patients. Whole-exome sequencing identified 233 candidate variants, from which 82 variants in 53 genes were prioritized for downstream analysis. Eighteen disease-modifying pathways were identified; two of the most enriched pathways were relevant for the nervous system, namely the neuregulin signaling and the agrin interactions at neuromuscular junction. Variants at PARD3, NFKB1, CHD5, ACTG1, CFAP57, DLGAP2, ITGB1, DIDO1 and CERS4 modulate age at onset in MJD, with those identified in CFAP57, ACTG1 and DIDO1 showing consistent effects across cohorts of different geographical origins. Network analyses of the nine novel MJD modifiers highlighted several important molecular interactions, including genes/proteins previously related with MJD pathogenesis, namely between ACTG1/APOE and VCP/ITGB1. We describe novel pathways, modifiers, and their interaction partners, providing a broad molecular portrait of age at onset modulation to be further exploited as new disease-modifying targets for MJD and related diseases.


Asunto(s)
Enfermedad de Machado-Joseph , Edad de Inicio , Alelos , ADN Helicasas/genética , Genotipo , Humanos , Enfermedad de Machado-Joseph/genética , Enfermedad de Machado-Joseph/patología , Proteínas del Tejido Nervioso/genética , Secuenciación del Exoma
6.
Biochem Biophys Res Commun ; 623: 170-175, 2022 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-35921708

RESUMEN

Dysregulation of autophagy, one of the major processes through which abnormal proteins are degraded, is a cardinal feature of synucleinopathies, including Lewy body diseases [Parkinson's disease (PD) and dementia with Lewy bodies (DLB)] and multiple system atrophy (MSA), which are characterized by the presence of abnormal α-synuclein in neurons and glial cells. Although several research groups have reported that Rubicon family proteins can regulate autophagosome-lysosome fusion or positioning, little is known about their involvement in synucleinopathies. In the present study, by studying patients with PD (N = 8), DLB (N = 13), and MSA (N = 5) and controls (N = 16), we explored the involvement of Rubicon family proteins [Rubicon, Pacer and differentially expressed in FDCP8 (DEF8)] in synucleinopathies. Immunohistochemical analysis showed that not only brainstem-type Lewy bodies but also cortical Lewy bodies were immunoreactive for DEF8 in Lewy body diseases, whereas Rubicon and Pacer were detectable in only a few brainstem-type Lewy bodies in PD. Glial cytoplasmic inclusions in patients with MSA were not immunoreactive for Rubicon, Pacer or DEF8. Immunoblotting showed significantly increased protein levels of DEF8 in the substantia nigra and putamen of patients with PD and the temporal cortex of patients with DLB. In addition, the smear band of DEF8 appeared in the insoluble fraction where that of phosphorylated α-synuclein was detected. These findings indicate the involvement of DEF8 in the formation of Lewy bodies. Quantitative and qualitative alterations in DEF8 may reflect the dysregulation of autophagy in Lewy body diseases.


Asunto(s)
Enfermedad por Cuerpos de Lewy , Atrofia de Múltiples Sistemas , Enfermedad de Parkinson , Sinucleinopatías , Autofagia , Encéfalo/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular , Cuerpos de Lewy/metabolismo , Enfermedad por Cuerpos de Lewy/metabolismo , Atrofia de Múltiples Sistemas/metabolismo , Enfermedad de Parkinson/metabolismo , alfa-Sinucleína/metabolismo
7.
Neuropathol Appl Neurobiol ; 48(7): e12844, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-35906771

RESUMEN

AIMS: Synaptic dysfunction in Parkinson's disease is caused by propagation of pathogenic α-synuclein between neurons. Previously, in multiple system atrophy (MSA), pathologically characterised by ectopic deposition of abnormal α-synuclein predominantly in oligodendrocytes, we demonstrated that the occurrence of memory impairment was associated with the number of α-synuclein-positive neuronal cytoplasmic inclusions (NCIs) in the hippocampus. In the present study, we aimed to investigate how abnormal α-synuclein in the hippocampus can lead to memory impairment. METHODS: We performed pathological and biochemical analyses using a mouse model of adult-onset MSA and human cases (MSA, N = 25; Parkinson's disease, N = 3; Alzheimer's disease, N = 2; normal controls, N = 11). In addition, the MSA model mice were examined behaviourally and physiologically. RESULTS: In the MSA model, inducible human α-synuclein was first expressed in oligodendrocytes and subsequently accumulated in the cytoplasm of excitatory hippocampal neurons (NCI-like structures) and their presynaptic nerve terminals with the development of memory impairment. α-Synuclein oligomers increased simultaneously in the hippocampus of the MSA model. Hippocampal dendritic spines also decreased in number, followed by suppression of long-term potentiation. Consistent with these findings obtained in the MSA model, post-mortem analysis of human MSA brain tissues showed that cases of MSA with memory impairment developed more NCIs in excitatory hippocampal neurons along with α-synuclein oligomers than those without. CONCLUSIONS: Our results provide new insights into the role of α-synuclein oligomers as a possible pathological cause of memory impairment in MSA.


Asunto(s)
Atrofia de Múltiples Sistemas , Enfermedad de Parkinson , Humanos , Atrofia de Múltiples Sistemas/patología , alfa-Sinucleína/metabolismo , Enfermedad de Parkinson/patología , Cuerpos de Inclusión/patología , Neuronas/patología , Encéfalo/patología
8.
Acta Neuropathol ; 143(3): 383-401, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34961893

RESUMEN

Frontotemporal lobar degeneration (FTLD) is a group of heterogeneous neurodegenerative disorders affecting the frontal and temporal lobes of the brain. Nuclear loss and cytoplasmic aggregation of the RNA-binding protein TDP-43 represents the major FTLD pathology, known as FTLD-TDP. To date, there is no effective treatment for FTLD-TDP due to an incomplete understanding of the molecular mechanisms underlying disease development. Here we compared postmortem tissue RNA-seq transcriptomes from the frontal cortex, temporal cortex, and cerebellum between 28 controls and 30 FTLD-TDP patients to profile changes in cell-type composition, gene expression and transcript usage. We observed downregulation of neuronal markers in all three regions of the brain, accompanied by upregulation of microglia, astrocytes, and oligodendrocytes, as well as endothelial cells and pericytes, suggesting shifts in both immune activation and within the vasculature. We validate our estimates of neuronal loss using neuropathological atrophy scores and show that neuronal loss in the cortex can be mainly attributed to excitatory neurons, and that increases in microglial and endothelial cell expression are highly correlated with neuronal loss. All our analyses identified a strong involvement of the cerebellum in the neurodegenerative process of FTLD-TDP. Altogether, our data provides a detailed landscape of gene expression alterations to help unravel relevant disease mechanisms in FTLD.


Asunto(s)
Demencia Frontotemporal , Degeneración Lobar Frontotemporal , Encéfalo/patología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Células Endoteliales/patología , Demencia Frontotemporal/patología , Degeneración Lobar Frontotemporal/patología , Humanos , Transcriptoma
9.
Brain ; 144(4): 1138-1151, 2021 05 07.
Artículo en Inglés | MEDLINE | ID: mdl-33822892

RESUMEN

We studied a subset of patients with autopsy-confirmed multiple system atrophy who presented a clinical picture that closely resembled either Parkinson's disease or progressive supranuclear palsy. These mimics are not captured by the current diagnostic criteria for multiple system atrophy. Among 218 autopsy-proven multiple system atrophy cases reviewed, 177 (81.2%) were clinically diagnosed and pathologically confirmed as multiple system atrophy (i.e. typical cases), while the remaining 41 (18.8%) had received an alternative clinical diagnosis, including Parkinson's disease (i.e. Parkinson's disease mimics; n = 16) and progressive supranuclear palsy (i.e. progressive supranuclear palsy mimics; n = 17). We also reviewed the clinical records of another 105 patients with pathologically confirmed Parkinson's disease or progressive supranuclear palsy, who had received a correct final clinical diagnosis (i.e. Parkinson's disease, n = 35; progressive supranuclear palsy-Richardson syndrome, n = 35; and progressive supranuclear palsy-parkinsonism, n = 35). We investigated 12 red flag features that would support a diagnosis of multiple system atrophy according to the current diagnostic criteria. Compared with typical multiple system atrophy, Parkinson's disease mimics more frequently had a good levodopa response and visual hallucinations. Vertical gaze palsy and apraxia of eyelid opening were more commonly observed in progressive supranuclear palsy mimics. Multiple logistic regression analysis revealed an increased likelihood of having multiple system atrophy [Parkinson's disease mimic versus typical Parkinson's disease, odds ratio (OR): 8.1; progressive supranuclear palsy mimic versus typical progressive supranuclear palsy, OR: 2.3] if a patient developed any one of seven selected red flag features in the first 10 years of disease. Severe autonomic dysfunction (orthostatic hypotension and/or urinary incontinence with the need for a urinary catheter) was more frequent in clinically atypical multiple system atrophy than other parkinsonian disorders (Parkinson's disease mimic versus typical Parkinson's disease, OR: 4.1; progressive supranuclear palsy mimic versus typical progressive supranuclear palsy, OR: 8.8). The atypical multiple system atrophy cases more frequently had autonomic dysfunction within 3 years of symptom onset than the pathologically confirmed patients with Parkinson's disease or progressive supranuclear palsy (Parkinson's disease mimic versus typical Parkinson's disease, OR: 4.7; progressive supranuclear palsy mimic versus typical progressive supranuclear palsy, OR: 2.7). Using all included clinical features and 21 early clinical features within 3 years of symptom onset, we developed decision tree algorithms with combinations of clinical pointers to differentiate clinically atypical cases of multiple system atrophy from Parkinson's disease or progressive supranuclear palsy.


Asunto(s)
Atrofia de Múltiples Sistemas/diagnóstico , Enfermedad de Parkinson/diagnóstico , Parálisis Supranuclear Progresiva/diagnóstico , Anciano , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Atrofia de Múltiples Sistemas/patología , Enfermedad de Parkinson/patología , Parálisis Supranuclear Progresiva/patología
10.
Neuropathol Appl Neurobiol ; 47(7): 897-909, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34318515

RESUMEN

Neurodegenerative movement disorders (NMDs) are age-dependent disorders that are characterised by the degeneration and loss of neurons, typically accompanied by pathological accumulation of different protein aggregates in the brain, which lead to motor symptoms. NMDs include Parkinson's disease, multiple system atrophy, progressive supranuclear palsy, and Huntington's disease, among others. Epigenetic modifications are responsible for functional gene regulation during development, adult life and ageing and have progressively been implicated in complex diseases such as cancer and more recently in neurodegenerative diseases, such as NMDs. DNA methylation is by far the most widely studied epigenetic modification and consists of the reversible addition of a methyl group to the DNA without changing the DNA sequence. Although this research field is still in its infancy in relation to NMDs, an increasing number of studies point towards a role for DNA methylation in disease processes. This review addresses recent advances in epigenetic and epigenomic research in NMDs, with a focus on human brain DNA methylation studies. We discuss the current understanding of the DNA methylation changes underlying these disorders, the potential for use of these DNA modifications in peripheral tissues as biomarkers in early disease detection, classification and progression as well as a promising role in future disease management and therapy.


Asunto(s)
Encéfalo/fisiopatología , Epigénesis Genética/genética , Enfermedad de Huntington/genética , Enfermedades Neurodegenerativas/genética , Envejecimiento/genética , Encéfalo/metabolismo , Metilación de ADN , Humanos , Enfermedad de Huntington/metabolismo , Enfermedades Neurodegenerativas/metabolismo
11.
Neuropathol Appl Neurobiol ; 47(5): 640-652, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33368549

RESUMEN

AIMS: Multiple system atrophy (MSA) is a fatal neurodegenerative disease. Similar to Parkinson's disease (PD), MSA is an α-synucleinopathy, and its pathological hallmark consists of glial cytoplasmic inclusions (GCIs) containing α-synuclein (SNCA) in oligodendrocytes. We previously identified consistent changes in myelin-associated oligodendrocyte basic protein (MOBP) and huntingtin interacting protein 1 (HIP1) DNA methylation status in MSA. We hypothesized that if differential DNA methylation at these loci is mechanistically relevant for MSA, it should have downstream consequences on gene regulation. METHODS: We investigated the relationship between MOBP and HIP1 DNA methylation and mRNA levels in cerebellar white matter from MSA and healthy controls. Additionally, we analysed protein expression using western blotting, immunohistochemistry and proximity ligation assays. RESULTS: We found decreased MOBP mRNA levels significantly correlated with increased DNA methylation in MSA. For HIP1, we found a distinct relationship between DNA methylation and gene expression levels in MSA compared to healthy controls, suggesting this locus may be subjected to epigenetic remodelling in MSA. Although soluble protein levels for MOBP and HIP1 in cerebellar white matter were not significantly different between MSA cases and controls, we found striking differences between MSA and other neurodegenerative diseases, including PD and Huntington's disease. We also found that MOBP and HIP1 are mislocalized into the GCIs in MSA, where they appear to interact with SNCA. CONCLUSIONS: This study supports a role for DNA methylation in downregulation of MOBP mRNA in MSA. Most importantly, the identification of MOBP and HIP1 as new constituents of GCIs emphasizes the relevance of these two loci to the pathogenesis of MSA.


Asunto(s)
Proteínas de Unión al ADN/metabolismo , Atrofia de Múltiples Sistemas/patología , Proteínas de la Mielina/metabolismo , Neuroglía/patología , alfa-Sinucleína/metabolismo , Humanos , Cuerpos de Inclusión/patología , Atrofia de Múltiples Sistemas/metabolismo , Proteínas de la Mielina/genética , Neuroglía/metabolismo , Oligodendroglía/patología , Enfermedad de Parkinson/patología , Sustancia Blanca/patología
12.
Mol Biol Rep ; 48(3): 2093-2104, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33742325

RESUMEN

Mutations in nuclear-encoded protein subunits of the mitochondrial ribosome are an increasingly recognised cause of oxidative phosphorylation system (OXPHOS) disorders. Among them, mutations in the MRPL44 gene, encoding a structural protein of the large subunit of the mitochondrial ribosome, have been identified in four patients with OXPHOS defects and early-onset hypertrophic cardiomyopathy with or without additional clinical features. A 23-year-old individual with cardiac and skeletal myopathy, neurological involvement, and combined deficiency of OXPHOS complexes in skeletal muscle was clinically and genetically investigated. Analysis of whole-exome sequencing data revealed a homozygous mutation in MRPL44 (c.467 T > G), which was not present in the biological father, and a region of homozygosity involving most of chromosome 2, raising the possibility of uniparental disomy. Short-tandem repeat and genome-wide SNP microarray analyses of the family trio confirmed complete maternal uniparental isodisomy of chromosome 2. Mitochondrial ribosome assembly and mitochondrial translation were assessed in patient derived-fibroblasts. These studies confirmed that c.467 T > G affects the stability or assembly of the large subunit of the mitochondrial ribosome, leading to impaired mitochondrial protein synthesis and decreased levels of multiple OXPHOS components. This study provides evidence of complete maternal uniparental isodisomy of chromosome 2 in a patient with MRPL44-related disease, and confirms that MRLP44 mutations cause a mitochondrial translation defect that may present as a multisystem disorder with neurological involvement.


Asunto(s)
Cromosomas Humanos Par 2/genética , Enfermedades Mitocondriales/genética , Proteínas Mitocondriales/genética , Proteínas Ribosómicas/genética , Disomía Uniparental/genética , Adolescente , Secuencia de Bases , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Preescolar , Femenino , Fibroblastos/patología , Homocigoto , Humanos , Lactante , Recién Nacido , Imagen por Resonancia Magnética , Enfermedades Mitocondriales/patología , Músculo Esquelético/metabolismo , Mutación/genética , Fosforilación Oxidativa , Biosíntesis de Proteínas , Adulto Joven
13.
Am J Hum Genet ; 101(3): 451-458, 2017 Sep 07.
Artículo en Inglés | MEDLINE | ID: mdl-28886343

RESUMEN

The metabotropic glutamate receptor 1 (mGluR1) is abundantly expressed in the mammalian central nervous system, where it regulates intracellular calcium homeostasis in response to excitatory signaling. Here, we describe heterozygous dominant mutations in GRM1, which encodes mGluR1, that are associated with distinct disease phenotypes: gain-of-function missense mutations, linked in two different families to adult-onset cerebellar ataxia, and a de novo truncation mutation resulting in a dominant-negative effect that is associated with juvenile-onset ataxia and intellectual disability. Crucially, the gain-of-function mutations could be pharmacologically modulated in vitro using an existing FDA-approved drug, Nitazoxanide, suggesting a possible avenue for treatment, which is currently unavailable for ataxias.


Asunto(s)
Regulación de la Expresión Génica/efectos de los fármacos , Mutación Missense/genética , Receptores de Glutamato Metabotrópico/genética , Ataxias Espinocerebelosas/genética , Tiazoles/farmacología , Antiparasitarios/farmacología , Femenino , Células HEK293 , Humanos , Masculino , Nitrocompuestos , Linaje , Transducción de Señal/efectos de los fármacos , Ataxias Espinocerebelosas/patología
14.
Acta Neuropathol ; 139(1): 135-156, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31535203

RESUMEN

Multiple system atrophy (MSA) is a fatal late-onset neurodegenerative disease. Although presenting with distinct pathological hallmarks, which in MSA consist of glial cytoplasmic inclusions (GCIs) containing fibrillar α-synuclein in oligodendrocytes, both MSA and Parkinson's disease are α-synucleinopathies. Pathologically, MSA can be categorized into striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA) or mixed subtypes. Despite extensive research, the regional vulnerability of the brain to MSA pathology remains poorly understood. Genetic, epigenetic and environmental factors have been proposed to explain which brain regions are affected by MSA, and to what extent. Here, we explored for the first time epigenetic changes in post-mortem brain tissue from MSA cases. We conducted a case-control study, and profiled DNA methylation in white mater from three brain regions characterized by severe-to-mild GCIs burden in the MSA mixed subtype (cerebellum, frontal lobe and occipital lobe). Our genome-wide approach using Illumina MethylationEPIC arrays and a powerful cross-region analysis identified 157 CpG sites and 79 genomic regions where DNA methylation was significantly altered in the MSA mixed-subtype cases. HIP1, LMAN2 and MOBP were amongst the most differentially methylated loci. We replicated these findings in an independent cohort and further demonstrated that DNA methylation profiles were perturbed in MSA mixed subtype, and also to variable degrees in the other pathological subtypes (OPCA and SND). Finally, our co-methylation network analysis revealed several molecular signatures (modules) significantly associated with MSA (disease status and pathological subtypes), and with neurodegeneration in the cerebellum. Importantly, the co-methylation module having the strongest association with MSA included a CpG in SNCA, the gene encoding α-synuclein. Altogether, our results provide the first evidence for DNA methylation changes contributing to the molecular processes altered in MSA, some of which are shared with other neurodegenerative diseases, and highlight potential novel routes for diagnosis and therapeutic interventions.


Asunto(s)
Metilación de ADN/genética , Proteínas de Unión al ADN/genética , Lectinas de Unión a Manosa/genética , Proteínas de Transporte de Membrana/genética , Atrofia de Múltiples Sistemas/genética , Proteínas de la Mielina/genética , Anciano , Encéfalo/metabolismo , Encéfalo/patología , Estudios de Casos y Controles , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Atrofia de Múltiples Sistemas/patología , Sustancia Blanca/metabolismo , Sustancia Blanca/patología , alfa-Sinucleína/genética
15.
Hum Mutat ; 39(2): 187-192, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29127725

RESUMEN

We report on a homozygous frameshift deletion in DDX59 (c.185del: p.Phe62fs*13) in a family presenting with orofaciodigital syndrome phenotype associated with a broad neurological involvement characterized by microcephaly, intellectual disability, epilepsy, and white matter signal abnormalities associated with cortical and subcortical ischemic events. DDX59 encodes a DEAD-box RNA helicase and its role in brain function and neurological diseases is unclear. We showed a reduction of mutant cDNA and perturbation of SHH signaling from patient-derived cell lines; furthermore, analysis of human brain gene expression provides evidence that DDX59 is enriched in oligodendrocytes and might act within pathways of leukoencephalopathies-associated genes. We also characterized the neuronal phenotype of the Drosophila model using mutant mahe, the homolog of human DDX59, and showed that mahe loss-of-function mutant embryos exhibit impaired development of peripheral and central nervous system. Taken together, our results support a conserved role of this DEAD-box RNA helicase in neurological function.


Asunto(s)
ARN Helicasas DEAD-box/genética , Mutación/genética , ARN Helicasas/genética , Adulto , Secuencia de Aminoácidos , Animales , Sistema Nervioso Central/metabolismo , Niño , Preescolar , Drosophila/genética , Femenino , Mutación del Sistema de Lectura/genética , Homocigoto , Humanos , Masculino , Datos de Secuencia Molecular , Adulto Joven
16.
Am J Hum Genet ; 96(6): 938-47, 2015 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-25983243

RESUMEN

Myoclonus-dystonia (M-D) is a rare movement disorder characterized by a combination of non-epileptic myoclonic jerks and dystonia. SGCE mutations represent a major cause for familial M-D being responsible for 30%-50% of cases. After excluding SGCE mutations, we identified through a combination of linkage analysis and whole-exome sequencing KCTD17 c.434 G>A p.(Arg145His) as the only segregating variant in a dominant British pedigree with seven subjects affected by M-D. A subsequent screening in a cohort of M-D cases without mutations in SGCE revealed the same KCTD17 variant in a German family. The clinical presentation of the KCTD17-mutated cases was distinct from the phenotype usually observed in M-D due to SGCE mutations. All cases initially presented with mild myoclonus affecting the upper limbs. Dystonia showed a progressive course, with increasing severity of symptoms and spreading from the cranio-cervical region to other sites. KCTD17 is abundantly expressed in all brain regions with the highest expression in the putamen. Weighted gene co-expression network analysis, based on mRNA expression profile of brain samples from neuropathologically healthy individuals, showed that KCTD17 is part of a putamen gene network, which is significantly enriched for dystonia genes. Functional annotation of the network showed an over-representation of genes involved in post-synaptic dopaminergic transmission. Functional studies in mutation bearing fibroblasts demonstrated abnormalities in endoplasmic reticulum-dependent calcium signaling. In conclusion, we demonstrate that the KCTD17 c.434 G>A p.(Arg145His) mutation causes autosomal dominant M-D. Further functional studies are warranted to further characterize the nature of KCTD17 contribution to the molecular pathogenesis of M-D.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Trastornos Distónicos/genética , Trastornos Distónicos/patología , Mutación Missense/genética , Canales de Potasio/genética , Secuencia de Bases , Encéfalo/metabolismo , Mapeo Cromosómico , Trastornos Distónicos/metabolismo , Exoma/genética , Femenino , Redes Reguladoras de Genes/genética , Genes Dominantes/genética , Alemania , Humanos , Masculino , Datos de Secuencia Molecular , Linaje , Análisis de Secuencia de ADN , Transmisión Sináptica/genética , Reino Unido
18.
Mov Disord ; 33(3): 482-488, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29392776

RESUMEN

BACKGROUND: We investigated a family that presented with an infantile-onset chorea-predominant movement disorder, negative for NKX2-1, ADCY5, and PDE10A mutations. METHODS: Phenotypic characterization and trio whole-exome sequencing was carried out in the family. RESULTS: We identified a homozygous mutation affecting the GAF-B domain of the 3',5'-cyclic nucleotide phosphodiesterase PDE2A gene (c.1439A>G; p.Asp480Gly) as the candidate novel genetic cause of chorea in the proband. PDE2A hydrolyzes cyclic adenosine/guanosine monophosphate and is highly expressed in striatal medium spiny neurons. We functionally characterized the p.Asp480Gly mutation and found that it severely decreases the enzymatic activity of PDE2A. In addition, we showed equivalent expression in human and mouse striatum of PDE2A and its homolog gene, PDE10A. CONCLUSIONS: We identified a loss-of-function homozygous mutation in PDE2A associated to early-onset chorea. Our findings possibly strengthen the role of cyclic adenosine monophosphate and cyclic guanosine monophosphate metabolism in striatal medium spiny neurons as a crucial pathophysiological mechanism in hyperkinetic movement disorders. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.


Asunto(s)
Corea/genética , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2/genética , Mutación/genética , Animales , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Salud de la Familia , Pruebas Genéticas , Humanos , Masculino , Hidrolasas Diéster Fosfóricas/genética , Hidrolasas Diéster Fosfóricas/metabolismo , ARN Mensajero/metabolismo
19.
Am J Hum Genet ; 94(1): 11-22, 2014 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-24360804

RESUMEN

Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of disorders with progressive extrapyramidal signs and neurological deterioration, characterized by iron accumulation in the basal ganglia. Exome sequencing revealed the presence of recessive missense mutations in COASY, encoding coenzyme A (CoA) synthase in one NBIA-affected subject. A second unrelated individual carrying mutations in COASY was identified by Sanger sequence analysis. CoA synthase is a bifunctional enzyme catalyzing the final steps of CoA biosynthesis by coupling phosphopantetheine with ATP to form dephospho-CoA and its subsequent phosphorylation to generate CoA. We demonstrate alterations in RNA and protein expression levels of CoA synthase, as well as CoA amount, in fibroblasts derived from the two clinical cases and in yeast. This is the second inborn error of coenzyme A biosynthesis to be implicated in NBIA.


Asunto(s)
Encéfalo/efectos de los fármacos , Exoma , Hierro/metabolismo , Degeneración Nerviosa/patología , Encéfalo/patología , Clonación Molecular , Coenzima A/metabolismo , Escherichia coli/genética , Femenino , Fibroblastos/metabolismo , Regulación de la Expresión Génica , Humanos , Masculino , Mitocondrias/enzimología , Mitocondrias/genética , Mutación Missense , Panteteína/análogos & derivados , Panteteína/metabolismo , Linaje , Fosforilación , Saccharomyces cerevisiae/genética , Transferasas/genética , Transferasas/metabolismo
20.
Am J Hum Genet ; 95(5): 590-601, 2014 Nov 06.
Artículo en Inglés | MEDLINE | ID: mdl-25439726

RESUMEN

Using a combination of exome sequencing and linkage analysis, we investigated an English family with two affected siblings in their 40s with recessive Charcot-Marie Tooth disease type 2 (CMT2). Compound heterozygous mutations in the immunoglobulin-helicase-µ-binding protein 2 (IGHMBP2) gene were identified. Further sequencing revealed a total of 11 CMT2 families with recessively inherited IGHMBP2 gene mutations. IGHMBP2 mutations usually lead to spinal muscular atrophy with respiratory distress type 1 (SMARD1), where most infants die before 1 year of age. The individuals with CMT2 described here, have slowly progressive weakness, wasting and sensory loss, with an axonal neuropathy typical of CMT2, but no significant respiratory compromise. Segregating IGHMBP2 mutations in CMT2 were mainly loss-of-function nonsense in the 5' region of the gene in combination with a truncating frameshift, missense, or homozygous frameshift mutations in the last exon. Mutations in CMT2 were predicted to be less aggressive as compared to those in SMARD1, and fibroblast and lymphoblast studies indicate that the IGHMBP2 protein levels are significantly higher in CMT2 than SMARD1, but lower than controls, suggesting that the clinical phenotype differences are related to the IGHMBP2 protein levels.


Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Exoma/genética , Modelos Moleculares , Mutación Missense/genética , Fenotipo , Adulto , Secuencia de Bases , Enfermedad de Charcot-Marie-Tooth/patología , Mapeo Cromosómico , Femenino , Haplotipos/genética , Humanos , Datos de Secuencia Molecular , Linaje , Mapeo de Interacción de Proteínas , Análisis de Secuencia de ADN , Nervio Sural/patología
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