Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 141
Filtrar
Mais filtros

Base de dados
País/Região como assunto
Tipo de documento
Intervalo de ano de publicação
1.
Nature ; 628(8009): 844-853, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38570685

RESUMO

Mitochondria are critical modulators of antiviral tolerance through the release of mitochondrial RNA and DNA (mtDNA and mtRNA) fragments into the cytoplasm after infection, activating virus sensors and type-I interferon (IFN-I) response1-4. The relevance of these mechanisms for mitochondrial diseases remains understudied. Here we investigated mitochondrial recessive ataxia syndrome (MIRAS), which is caused by a common European founder mutation in DNA polymerase gamma (POLG1)5. Patients homozygous for the MIRAS variant p.W748S show exceptionally variable ages of onset and symptoms5, indicating that unknown modifying factors contribute to disease manifestation. We report that the mtDNA replicase POLG1 has a role in antiviral defence mechanisms to double-stranded DNA and positive-strand RNA virus infections (HSV-1, TBEV and SARS-CoV-2), and its p.W748S variant dampens innate immune responses. Our patient and knock-in mouse data show that p.W748S compromises mtDNA replisome stability, causing mtDNA depletion, aggravated by virus infection. Low mtDNA and mtRNA release into the cytoplasm and a slow IFN response in MIRAS offer viruses an early replicative advantage, leading to an augmented pro-inflammatory response, a subacute loss of GABAergic neurons and liver inflammation and necrosis. A population databank of around 300,000 Finnish individuals6 demonstrates enrichment of immunodeficient traits in carriers of the POLG1 p.W748S mutation. Our evidence suggests that POLG1 defects compromise antiviral tolerance, triggering epilepsy and liver disease. The finding has important implications for the mitochondrial disease spectrum, including epilepsy, ataxia and parkinsonism.


Assuntos
Alelos , DNA Polimerase gama , Vírus da Encefalite Transmitidos por Carrapatos , Herpesvirus Humano 1 , Tolerância Imunológica , SARS-CoV-2 , Animais , Feminino , Humanos , Masculino , Camundongos , Idade de Início , COVID-19/imunologia , COVID-19/virologia , COVID-19/genética , DNA Polimerase gama/genética , DNA Polimerase gama/imunologia , DNA Polimerase gama/metabolismo , DNA Mitocondrial/imunologia , DNA Mitocondrial/metabolismo , Vírus da Encefalite Transmitidos por Carrapatos/imunologia , Encefalite Transmitida por Carrapatos/genética , Encefalite Transmitida por Carrapatos/imunologia , Encefalite Transmitida por Carrapatos/virologia , Efeito Fundador , Técnicas de Introdução de Genes , Herpes Simples/genética , Herpes Simples/imunologia , Herpes Simples/virologia , Herpesvirus Humano 1/imunologia , Tolerância Imunológica/genética , Tolerância Imunológica/imunologia , Imunidade Inata/genética , Imunidade Inata/imunologia , Interferon Tipo I/imunologia , Doenças Mitocondriais/enzimologia , Doenças Mitocondriais/genética , Doenças Mitocondriais/imunologia , Mutação , RNA Mitocondrial/imunologia , RNA Mitocondrial/metabolismo , SARS-CoV-2/imunologia
2.
Ann Neurol ; 95(5): 843-848, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38501694

RESUMO

When effective treatments against neurodegenerative diseases become a reality, it will be important to know the age these pathologies begin to develop. We investigated alpha-synuclein pathology in brain tissue of the Tampere Sudden Death Study-unselected forensic autopsies on individuals living outside hospital institutions in Finland. Of 562 (16-95 years) participants, 42 were positive for Lewy-related pathology (LRP). The youngest LRP case was aged 54 years, and the frequency of LRP in individuals aged ≥50 years was 9%. This forensic autopsy study indicates LRP starts already in middle age and is more common than expected in the ≥50 years-of-age non-hospitalized population. ANN NEUROL 2024;95:843-848.


Assuntos
Morte Súbita , Doença por Corpos de Lewy , alfa-Sinucleína , Humanos , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Idoso , Masculino , Feminino , Finlândia/epidemiologia , Morte Súbita/patologia , Adolescente , Doença por Corpos de Lewy/patologia , Doença por Corpos de Lewy/metabolismo , alfa-Sinucleína/metabolismo , Adulto , Adulto Jovem , Encéfalo/patologia , Encéfalo/metabolismo , Autopsia , Corpos de Lewy/patologia
3.
Brain ; 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38938199

RESUMO

Population-based cohort studies are essential for understanding the pathological basis of dementia in older populations. Previous studies have shown that limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) increases with age, but there have been only a few studies, which have investigated this entity in a population-based setting. Here we studied the frequency of LATE-NC and its associations with other brain pathologies and cognition in a population aged ≥ 85 years. The population-based Vantaa 85+ study cohort includes all 601 individuals aged ≥ 85 years who were living in Vantaa, Finland in 1991. A neuropathological examination was performed on 304 subjects (50.5%) and LATE-NC staging was possible in 295 of those. Dementia status and Mini-Mental State Examination (MMSE) scores were defined in the baseline study and 3 follow-ups (1994-99). The LATE-NC stages were determined based on TDP-43 immunohistochemistry, according to recently updated recommendations. Arteriolosclerosis was digitally assessed by calculating the average sclerotic index of five random small arterioles in amygdala and hippocampal regions, and frontal white matter. The association of LATE-NC with arteriolosclerosis and previously determined neuropathological variables including Alzheimer's disease neuropathological change (ADNC), Lewy-related pathology (LRP), hippocampal sclerosis (HS), and cerebral amyloid angiopathy (CAA), and cognitive variables were analysed by Fisher's exact test, linear and logistic regression (univariate and multivariate) models. LATE-NC was found in 189 of 295 subjects (64.1%). Stage 2 was the most common (28.5%) and stage 3 the second most common (12.9%), whereas stages 1a, 1b and 1c were less common (9.5%, 5.1% and 8.1%, respectively). Stages 1a (P < 0.01), 2 (P < 0.001) and 3 (P < 0.001) were significantly associated with dementia and lower MMSE scores. LATE-NC was associated with ADNC (P < 0.001), HS (P < 0.001), diffuse neocortical LRP (P < 0.002), and arteriolosclerosis in amygdala (P < 0.02). In most cases LATE-NC occurred in combination alongside other neuropathological changes. There were only six subjects with dementia who had LATE-NC without high levels of ADNC or LRP (2% of the cohort, 3% of the cases with dementia), and five of these had HS. In all multivariate models, LATE-NC was among the strongest independent predictors of dementia. When LATE-NC and ADNC were assessed in a multivariate model without other dementia-associated pathologies, the attributable risk was higher for LATE-NC than ADNC (24.2% vs. 18.6%). This population-based study provides evidence that LATE-NC is very common and one of the most significant determinants of dementia in the general late-life aged population.

4.
Brain ; 145(7): 2301-2312, 2022 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-35373813

RESUMO

Pathogenic variants in A Disintegrin And Metalloproteinase (ADAM) 22, the postsynaptic cell membrane receptor for the glycoprotein leucine-rich repeat glioma-inactivated protein 1 (LGI1), have been recently associated with recessive developmental and epileptic encephalopathy. However, so far, only two affected individuals have been described and many features of this disorder are unknown. We refine the phenotype and report 19 additional individuals harbouring compound heterozygous or homozygous inactivating ADAM22 variants, of whom 18 had clinical data available. Additionally, we provide follow-up data from two previously reported cases. All affected individuals exhibited infantile-onset, treatment-resistant epilepsy. Additional clinical features included moderate to profound global developmental delay/intellectual disability (20/20), hypotonia (12/20) and delayed motor development (19/20). Brain MRI findings included cerebral atrophy (13/20), supported by post-mortem histological examination in patient-derived brain tissue, cerebellar vermis atrophy (5/20), and callosal hypoplasia (4/20). Functional studies in transfected cell lines confirmed the deleteriousness of all identified variants and indicated at least three distinct pathological mechanisms: (i) defective cell membrane expression; (ii) impaired LGI1-binding; and/or (iii) impaired interaction with the postsynaptic density protein PSD-95. We reveal novel clinical and molecular hallmarks of ADAM22 deficiency and provide knowledge that might inform clinical management and early diagnostics.


Assuntos
Proteínas ADAM , Encefalopatias , Epilepsia Resistente a Medicamentos , Proteínas do Tecido Nervoso , Proteínas ADAM/genética , Proteínas ADAM/metabolismo , Atrofia , Encefalopatias/genética , Proteína 4 Homóloga a Disks-Large , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo
5.
Neuropathol Appl Neurobiol ; 48(3): e12788, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34927275

RESUMO

AIMS: Few studies have investigated primary age-related tauopathy (PART) in a population-based setting. Here, we assessed its prevalence, genetic background, comorbidities and features of cognitive decline in an unselected elderly population. METHODS: The population-based Vantaa 85+ study includes all 601 inhabitants of Vantaa aged ≥ 85 years in 1991. Neuropathological assessment was possible in 301. Dementia (DSM IIIR criteria) and Mini-Mental State Examination (MMSE) scores were assessed at the baseline of the study and follow-ups. PART subjects were identified according to the criteria by Crary et al and were compared with subjects with mild and severe Alzheimer's disease (AD) neuropathological changes. The effects of other neuropathologies were taken into account using multivariate and sensitivity assays. Genetic analyses included APOE genotypes and 29 polymorphisms of the MAPT 3' untranslated region (3'UTR region). RESULTS: The frequency of PART was 20% (n = 61/301, definite PART 5%). When PART subjects were compared with those with severe AD pathology, dementia was less common, its age at onset was higher and duration shorter. No such differences were seen when compared with those with milder AD pathology. However, both AD groups showed a steeper decline in MMSE scores in follow-ups compared with PART. APOE ε4 frequency was lower, and APOE ε2 frequency higher in the PART group compared with each AD group. The detected nominally significant associations between PART and two MAPT 3'UTR polymorphisms and haplotypes did not survive Bonferroni correction. CONCLUSIONS: PART is common among very elderly. PART subjects differ from individuals with AD-type changes in the pattern of cognitive decline, associated genetic and neuropathological features.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Tauopatias , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Apolipoproteína E4/genética , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/genética , Finlândia/epidemiologia , Genótipo , Humanos , Tauopatias/epidemiologia , Tauopatias/genética , Tauopatias/patologia
6.
Acta Neurol Scand ; 145(1): 63-72, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34418069

RESUMO

OBJECTIVES: Clinical diagnostics in adults with hereditary neurological diseases is complicated by clinical and genetic heterogeneity, as well as lifestyle effects. Here, we evaluate the effectiveness of exome sequencing and clinical costs in our difficult-to-diagnose adult patient cohort. Additionally, we expand the phenotypic and genetic spectrum of hereditary neurological disorders in Finland. METHODS: We performed clinical exome sequencing (CES) to 100 adult patients from Finland with neurological symptoms of suspected genetic cause. The patients were classified as myopathy (n = 57), peripheral neuropathy (n = 16), ataxia (n = 15), spastic paraplegia (n = 4), Parkinsonism (n = 3), and mixed (n = 5). In addition, we gathered the costs of prior diagnostic work-up to retrospectively assess the cost-effectiveness of CES as a first-line diagnostic tool. RESULTS: The overall diagnostic yield of CES was 27%. Pathogenic variants were found for 14 patients (in genes ANO5, CHCHD10, CLCN1, DES, DOK7, FKBP14, POLG, PYROXD1, SCN4A, TUBB3, and TTN) and likely pathogenic previously undescribed variants for 13 patients (in genes ABCD1, AFG3L2, ATL1, CACNA1A, COL6A1, DYSF, IRF2BPL, KCNA1, MT-ATP6, SAMD9L, SGCB, and TPM2). Age of onset below 40 years increased the probability of finding a genetic cause. Our cost evaluation of prior diagnostic work-up suggested that early CES would be cost-effective in this patient group, in which diagnostic costs increase linearly with prolonged investigations. CONCLUSIONS: Based on our results, CES is a cost-effective, powerful first-line diagnostic tool in establishing the molecular diagnosis in adult neurological patients with variable symptoms. Importantly, CES can markedly shorten the diagnostic odysseys of about one third of patients.


Assuntos
Doenças do Sistema Nervoso , Transtornos Parkinsonianos , Proteases Dependentes de ATP , ATPases Associadas a Diversas Atividades Celulares , Adulto , Anoctaminas , Proteínas de Transporte , Estudos de Coortes , Exoma/genética , Humanos , Mutação , Canal de Sódio Disparado por Voltagem NAV1.4 , Doenças do Sistema Nervoso/diagnóstico , Doenças do Sistema Nervoso/genética , Proteínas Nucleares , Peptidilprolil Isomerase , Estudos Retrospectivos
7.
Hum Mol Genet ; 26(17): 3352-3361, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28645153

RESUMO

Leigh syndrome is a severe infantile encephalopathy with an exceptionally variable genetic background. We studied the exome of a child manifesting with Leigh syndrome at one month of age and progressing to death by the age of 2.4 years, and identified novel compound heterozygous variants in PNPT1, encoding the polynucleotide phosphorylase (PNPase). Expression of the wild type PNPT1 in the subject's myoblasts functionally complemented the defects, and the pathogenicity was further supported by structural predictions and protein and RNA analyses. PNPase is a key enzyme in mitochondrial RNA metabolism, with suggested roles in mitochondrial RNA import and degradation. The variants were predicted to locate in the PNPase active site and disturb the RNA processing activity of the enzyme. The PNPase trimer formation was not affected, but specific RNA processing intermediates derived from mitochondrial transcripts of the ND6 subunit of Complex I, as well as small mRNA fragments, accumulated in the subject's myoblasts. Mitochondrial RNA processing mediated by the degradosome consisting of hSUV3 and PNPase is poorly characterized, and controversy on the role and location of PNPase within human mitochondria exists. Our evidence indicates that PNPase activity is essential for the correct maturation of the ND6 transcripts, and likely for the efficient removal of degradation intermediates. Loss of its activity will result in combined respiratory chain deficiency, and a classic respiratory chain-deficiency-associated disease, Leigh syndrome, indicating an essential role for the enzyme for normal function of the mitochondrial respiratory chain.


Assuntos
Exorribonucleases/genética , Exorribonucleases/metabolismo , Doença de Leigh/genética , Pré-Escolar , Exoma , Exorribonucleases/química , Feminino , Expressão Gênica , Humanos , Lactente , Recém-Nascido , Doença de Leigh/metabolismo , Mitocôndrias/metabolismo , Doenças Mitocondriais/genética , Polirribonucleotídeo Nucleotidiltransferase , RNA/metabolismo , RNA Mensageiro/metabolismo , RNA Mitocondrial
8.
Am J Hum Genet ; 99(3): 683-694, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27545674

RESUMO

The ubiquitin fold modifier 1 (UFM1) cascade is a recently identified evolutionarily conserved ubiquitin-like modification system whose function and link to human disease have remained largely uncharacterized. By using exome sequencing in Finnish individuals with severe epileptic syndromes, we identified pathogenic compound heterozygous variants in UBA5, encoding an activating enzyme for UFM1, in two unrelated families. Two additional individuals with biallelic UBA5 variants were identified from the UK-based Deciphering Developmental Disorders study and one from the Northern Finland Intellectual Disability cohort. The affected individuals (n = 9) presented in early infancy with severe irritability, followed by dystonia and stagnation of development. Furthermore, the majority of individuals display postnatal microcephaly and epilepsy and develop spasticity. The affected individuals were compound heterozygous for a missense substitution, c.1111G>A (p.Ala371Thr; allele frequency of 0.28% in Europeans), and a nonsense variant or c.164G>A that encodes an amino acid substitution p.Arg55His, but also affects splicing by facilitating exon 2 skipping, thus also being in effect a loss-of-function allele. Using an in vitro thioester formation assay and cellular analyses, we show that the p.Ala371Thr variant is hypomorphic with attenuated ability to transfer the activated UFM1 to UFC1. Finally, we show that the CNS-specific knockout of Ufm1 in mice causes neonatal death accompanied by microcephaly and apoptosis in specific neurons, further suggesting that the UFM1 system is essential for CNS development and function. Taken together, our data imply that the combination of a hypomorphic p.Ala371Thr variant in trans with a loss-of-function allele in UBA5 underlies a severe infantile-onset encephalopathy.


Assuntos
Alelos , Encefalopatias/genética , Encefalopatias/metabolismo , Mutação/genética , Proteínas/genética , Enzimas Ativadoras de Ubiquitina/genética , Ubiquitina/metabolismo , Animais , Animais Recém-Nascidos , Apoptose , Encefalopatias/patologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Estudos de Coortes , Epilepsia/genética , Exoma/genética , Éxons/genética , Fibroblastos/metabolismo , Fibroblastos/patologia , Finlândia , Frequência do Gene , Heterozigoto , Humanos , Lactente , Deficiência Intelectual/genética , Camundongos , Camundongos Knockout , Microcefalia/genética , Microcefalia/patologia , Neurônios/metabolismo , Neurônios/patologia , Proteínas/metabolismo , Espasmos Infantis/genética , Espasmos Infantis/metabolismo
9.
Acta Neuropathol ; 138(5): 771-782, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31494694

RESUMO

According to a generally accepted concept Lewy-related pathology (LRP) follows hierarchical caudo-rostral progression. LRP is also frequently present concomitantly with Alzheimer's disease (AD), and it has been hypothesized that AD-associated LRP forms a distinct type of α-synucleinopathy, where LRP originates in the amygdala. The frequency of distinct forms of LRP progression types has not been studied in a population-based setting. We investigated the distribution and progression of LRP and its relation to AD pathology and apolipoprotein (APOE) ε4 in a population-based sample of Finns aged over 85 years (N = 304). Samples from spinal cord to neocortical areas representing 11 anatomical sites without any hierarchical selection were analyzed immunohistochemically (α-synuclein antibody clone 5G4). LRP was present in 124 individuals (41%) and according to DLB Consortium guidelines 19 of them were categorized as brainstem, 10 amygdala-predominant, 41 limbic, and 43 diffuse neocortical type, whereas 11 could not be classified. To determine the LRP progression patterns, a systematic anatomical scoring was carried out by taking into account the densities of the semiquantitative LRP scores in each anatomic site. With this scoring 123 (99%) subjects could be classified into two progression pattern types: 67% showed caudo-rostral and 32% amygdala-based progression. The unsupervised statistical K-means cluster analysis was used as a supplementary test and supported the presence of two progression patterns and had a 90% overall concordance with the systematic anatomical scoring method. Severe Braak NFT stage, high CERAD score and APOE ε4 were significantly (all p < 0.00001) associated with amygdala-based, but not with caudo-rostral progression type (all p > 0.2). This population-based study demonstrates two distinct common LRP progression patterns in the very elderly population. The amygdala-based pattern was associated with APOE ε4 and AD pathology. The results confirm the previous progression hypotheses but also widen the concept of the AD-associated LRP.


Assuntos
Doença de Alzheimer/patologia , Corpos de Lewy/patologia , Doença por Corpos de Lewy/patologia , Doença de Parkinson/patologia , Idoso de 80 Anos ou mais , Encéfalo/patologia , Progressão da Doença , Feminino , Humanos , Masculino
10.
Am J Med Genet A ; 179(7): 1362-1365, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31059209

RESUMO

Fetal akinesia deformation sequence (FADS) and lethal multiple pterygium syndrome (LMPS) are clinically overlapping syndromes manifesting with reduced or absent fetal movement, arthrogryposis, and several anomalies during fetal life. The etiology of these syndromes is heterogeneous, and in many cases it remains unknown. In order to determine the genetic etiology of FADS in two fetuses with fetal akinesia, arthrogryposis, edema, and partial cleft palate, we utilized exome sequencing. Our investigations revealed a homozygous nonsense variant [c.1116C>A, p.(Cys372Ter)] in the SLC18A3 gene, which encodes for the vesicular acetylcholine transporter (VAChT) responsible for active transport of acetylcholine in the neuromuscular junction. This is the first description of a nonsense variant in the SLC18A3 gene, as only missense variants and whole gene deletions have been previously identified in patients. The previously detected SLC18A3 defects have been associated with congenital myasthenic syndromes, and therefore our findings extend the clinical spectrum of SLC18A3 defects to severe prenatal phenotypes. Our findings suggest that nonsense variants in SLC18A3 cause a more severe phenotype than missense variants and are in line with previous studies showing a lethal phenotype in VAChT knockout mice. Our results underline the importance of including SLC18A3 sequencing in the differential diagnostics of fetuses with arthrogryposis, FADS, or LMPS of unknown etiology.


Assuntos
Artrogripose , Mutação de Sentido Incorreto , Proteínas Vesiculares de Transporte de Acetilcolina/genética , Animais , Feminino , Humanos , Camundongos , Camundongos Knockout , Gravidez
11.
Emerg Infect Dis ; 24(5): 946-948, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29664395

RESUMO

In most locations except for Russia, tick-borne encephalitis is mainly caused by the European virus subtype. In 2015, fatal infections caused by European and Siberian tick-borne encephalitis virus subtypes in the same Ixodes ricinus tick focus in Finland raised concern over further spread of the Siberian subtype among widespread tick species.


Assuntos
Vírus da Encefalite Transmitidos por Carrapatos/genética , Encefalite Transmitida por Carrapatos/epidemiologia , Encefalite Transmitida por Carrapatos/virologia , Adulto , Idoso , Animais , Evolução Fatal , Feminino , Finlândia/epidemiologia , Humanos , Masculino , RNA Viral/genética , RNA Viral/isolamento & purificação , Carrapatos/virologia
12.
Brain ; 140(5): 1267-1279, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28335020

RESUMO

Progressive encephalopathy with oedema, hypsarrhythmia, and optic atrophy (PEHO) syndrome is an early childhood onset, severe autosomal recessive encephalopathy characterized by extreme cerebellar atrophy due to almost total granule neuron loss. By combining homozygosity mapping in Finnish families with Sanger sequencing of positional candidate genes and with exome sequencing a homozygous missense substitution of leucine for serine at codon 31 in ZNHIT3 was identified as the primary cause of PEHO syndrome. ZNHIT3 encodes a nuclear zinc finger protein previously implicated in transcriptional regulation and in small nucleolar ribonucleoprotein particle assembly and thus possibly to pre-ribosomal RNA processing. The identified mutation affects a highly conserved amino acid residue in the zinc finger domain of ZNHIT3. Both knockdown and genome editing of znhit3 in zebrafish embryos recapitulate the patients' cerebellar defects, microcephaly and oedema. These phenotypes are rescued by wild-type, but not mutant human ZNHIT3 mRNA, suggesting that the patient missense substitution causes disease through a loss-of-function mechanism. Transfection of cell lines with ZNHIT3 expression vectors showed that the PEHO syndrome mutant protein is unstable. Immunohistochemical analysis of mouse cerebellar tissue demonstrated ZNHIT3 to be expressed in proliferating granule cell precursors, in proliferating and post-mitotic granule cells, and in Purkinje cells. Knockdown of Znhit3 in cultured mouse granule neurons and ex vivo cerebellar slices indicate that ZNHIT3 is indispensable for granule neuron survival and migration, consistent with the zebrafish findings and patient neuropathology. These results suggest that loss-of-function of a nuclear regulator protein underlies PEHO syndrome and imply that establishment of its spatiotemporal interaction targets will be the basis for developing therapeutic approaches and for improved understanding of cerebellar development.


Assuntos
Edema Encefálico/genética , Edema Encefálico/patologia , Cerebelo/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Neurônios/patologia , Proteínas Nucleares/genética , Proteínas Nucleares/fisiologia , Atrofia Óptica/genética , Atrofia Óptica/patologia , Espasmos Infantis/genética , Espasmos Infantis/patologia , Animais , Complexo do Signalossomo COP9 , Movimento Celular/genética , Movimento Celular/fisiologia , Sobrevivência Celular/genética , Sobrevivência Celular/fisiologia , Cerebelo/metabolismo , Edema/complicações , Edema/genética , Exoma/genética , Edição de Genes , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Microcefalia/complicações , Microcefalia/genética , Mutação de Sentido Incorreto/genética , Mutação de Sentido Incorreto/fisiologia , Neurônios/metabolismo , Proteínas Nucleares/biossíntese , Análise de Sequência de DNA , Fatores de Transcrição/biossíntese , Peixe-Zebra
14.
Am J Med Genet A ; 170(6): 1433-8, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26888048

RESUMO

We report a 10-year-old girl presenting with severe neonatal hypertrophic cardiomyopathy (HCM), feeding difficulties, mildly abnormal facial features, and progressive skeletal muscle symptoms but with normal cognitive development. Targeted oligonucleotide-selective sequencing of 101 cardiomyopathy genes revealed the genetic diagnosis, and the mutation was verified by Sanger sequencing in the patient and her parents. To offer insights into the potential mechanism of patient mutation, protein structural analysis was performed using the resolved structure of human activated HRAS protein with bound GTP analogue (PDB id 5P21) in Discovery Studio 4.5 (Dassault Systèmes Biovia, San Diego, CA). The patient with hypertrophic cardiomyopathy and normal cognitive development was diagnosed with an HRAS mutation c.173C>T (p.T58I), a milder variant of Costello syndrome affecting a highly conserved amino acid, threonine 58. Our analysis suggests that the p.G12 mutations slow GTP hydrolysis rendering HRAS unresponsive to GTPase activating proteins, and resulting in permanently active state. The p.T58I mutation likely affects binding of guanidine-nucleotide-exchange factors, thereby promoting the active state but also allowing for slow inactivation. Patients with the HRAS mutation c.173C>T (p.T58I) might go undiagnosed because of the milder phenotype compared with other mutations causing Costello syndrome. We expand the clinical and molecular picture of the rare HRAS mutation by reporting the first case in Europe and the fourth case in the literature. Our protein structure analysis offers insights into the mechanism of the mildly activating p.T58I mutation. © 2016 Wiley Periodicals, Inc.


Assuntos
Cardiomiopatia Hipertrófica/diagnóstico , Cardiomiopatia Hipertrófica/genética , Síndrome de Costello/diagnóstico , Síndrome de Costello/genética , Mutação , Fenótipo , Proteínas Proto-Oncogênicas p21(ras)/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Alelos , Biomarcadores , Análise Mutacional de DNA , Ecocardiografia , Estudos de Associação Genética , Testes Genéticos , Genótipo , Humanos , Recém-Nascido , Masculino , Radiografia Torácica , Índice de Gravidade de Doença
15.
Am J Obstet Gynecol ; 215(6): 768.e1-768.e8, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27457118

RESUMO

BACKGROUND: Provoked vestibulodynia manifests as allodynia of the vulvar vestibular mucosa. The exact mechanisms that result in altered pain sensation are unknown. Recently, we demonstrated the presence of secondary lymphoid tissue, which is the vestibule-associated lymphoid tissue in the vestibular mucosa, and showed that this tissue becomes activated in provoked vestibulodynia. OBJECTIVE: The purpose of this study was to examine whether expression of intraepithelial nerve fibers and nerve growth factor are related to immune activation in provoked vestibulodynia. STUDY DESIGN: Vestibular mucosal specimens were obtained from 27 patients with severe provoked vestibulodynia that was treated by vestibulectomy and from 15 control subjects. We used antibodies against the protein gene product 9.5, the neuron specific neurofilament, and nerve growth factor for immunohistochemistry to detect intraepithelial nerve fibers and nerve growth factor expressing immune cells in the vestibular mucosa. For intraepithelial nerve fibers, we determined their linear density (fiber counts per millimeter of the outer epithelial surface, protein gene product 9.5) or presence (neuron specific neurofilament). Nerve growth factor was analyzed by counting the staining-positive immune cells. Antibodies against CD20 (B lymphocytes) and CD3 (T lymphocytes) were used to identify and locate mucosal areas with increased density of lymphocytes and the presence of germinal centers (ie, signs of immune activation). B-cell activation index was used to describe the overall intensity of B-cell infiltration. RESULTS: We found more protein gene product 9.5-positive intraepithelial fibers in vestibulodynia than in the control samples (6.3/mm [range, 0.0-15.8] vs 2.0/mm [range, 0.0-12.0]; P=.006). Neuron specific neurofilament -positive intraepithelial fibers were found in 17 of 27 vestibulodynia cases (63.0%) and in none of the control cases. Protein gene product 9.5-positive intraepithelial fibers were more common in samples with more pronounced immune activation. The density of these fibers was higher in samples with than without germinal centers (6.1/mm [range, 4.3-15.8] vs 3.0/mm [range, 0.0-13.4]; P=.020). A positive correlation between the fiber density and B-cell activation index score of the sample was found (Spearman's Rho, 0.400; P=.004; R2=0.128). No significant difference, however, was found in the density or presence of nerve fibers between samples with high and low T-cell densities. We identified areas of minor and major vestibular glands in 16 of the patient samples and in 1 control sample. Protein gene product 9.5-positive nerve fibers were found more often in glandular epithelium surrounded by B-cell infiltration than in glands without B cells (P=.013). Also, the presence of neuron specific neurofilament-positive fibers in glandular epithelium was associated with B-cell infiltrates (P=.053). Nerve growth factor-positive immune cells were more common in mucosal areas with than without B-cell infiltration and intraepithelial nerve fibers. CONCLUSION: Excessive epithelial nerve growth in provoked vestibulodynia is associated with increased B-cell infiltration and the presence of germinal centers. This supports the fundamental role of immune activation in provoked vestibulodynia.


Assuntos
Epitélio/imunologia , Tecido Linfoide/imunologia , Mucosa/imunologia , Fibras Nervosas/imunologia , Fator de Crescimento Neural/imunologia , Vulvodinia/imunologia , Adolescente , Adulto , Estudos de Casos e Controles , Epitélio/inervação , Epitélio/metabolismo , Epitélio/patologia , Feminino , Humanos , Imuno-Histoquímica , Tecido Linfoide/metabolismo , Pessoa de Meia-Idade , Mucosa/inervação , Mucosa/metabolismo , Mucosa/patologia , Fibras Nervosas/patologia , Fator de Crescimento Neural/metabolismo , Vulva/imunologia , Vulva/inervação , Vulva/metabolismo , Vulva/patologia , Vulvodinia/metabolismo , Vulvodinia/patologia , Adulto Jovem
16.
Hum Mol Genet ; 22(15): 2975-83, 2013 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-23562820

RESUMO

Inherited peripheral neuropathies are a heterogeneous group of disorders that can affect patients of all ages. Children with inherited neuropathy often develop severe disability, but the genetic causes of recessive early-onset axonal neuropathies are not fully known. We have taken a whole-exome sequencing approach to identify causative disease mutations in single patients with early-onset axonal neuropathy. Here, we report compound heterozygous mutations in the tripartite motif containing 2 (TRIM2) gene in a patient with childhood-onset axonal neuropathy, low weight and small muscle mass. We show that the patient fibroblasts are practically devoid of TRIM2, through mRNA and protein instability caused by the mutations. TRIM2 is an E3 ubiquitin ligase that ubiquitinates neurofilament light chain, a component of the intermediate filament in axons. Resembling the findings in our patient's sural nerve biopsy, Trim2-gene trap mice showed axonopathy with accumulations of neurofilaments inside axons. Our results suggest that loss-of-function mutations in TRIM2 are a cause of axonal neuropathy, which we propose to develop as a consequence of axonal accumulation of neurofilaments, secondary to lack of its ubiquitination by TRIM2.


Assuntos
Axônios/metabolismo , Doença de Charcot-Marie-Tooth/genética , Proteínas Nucleares/deficiência , Adolescente , Axônios/patologia , Biópsia , Doença de Charcot-Marie-Tooth/diagnóstico , Exoma , Feminino , Fibroblastos/metabolismo , Humanos , Mutação , Proteínas de Neurofilamentos/metabolismo , Estabilidade de RNA , Análise de Sequência de DNA , Nervo Sural/metabolismo , Nervo Sural/patologia
17.
Neuropathology ; 35(1): 70-4, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25377279

RESUMO

Cerebral amyloid angiopathy (CAA) predisposes to symptomatic intracerebral hemorrhage (sICH) after combined thrombolytic and anticoagulant treatment of acute myocardial infarction. However, the role of CAA in stroke thrombolysis has not been established. Here, we describe a confirmed case of CAA-related hemorrhage in a patient receiving thrombolysis for acute ischemic stroke. On autopsy, immunohistochemistry revealed amyloid-ß positive staining in thickened cortical and meningeal arteries at sites of hemorrhage. Further research is urgently needed to determine the hemorrhage risk related to CAA in stroke thrombolysis and develop better diagnostic tools to identify CAA in the emergency room.


Assuntos
Isquemia Encefálica/complicações , Angiopatia Amiloide Cerebral/complicações , Hemorragias Intracranianas/complicações , Acidente Vascular Cerebral/complicações , Terapia Trombolítica/efeitos adversos , Idoso , Isquemia Encefálica/tratamento farmacológico , Angiopatia Amiloide Cerebral/tratamento farmacológico , Angiopatia Amiloide Cerebral/patologia , Evolução Fatal , Feminino , Humanos , Hemorragias Intracranianas/tratamento farmacológico , Hemorragias Intracranianas/patologia , Acidente Vascular Cerebral/tratamento farmacológico
18.
Duodecim ; 131(5): 465-74, 2015.
Artigo em Fi | MEDLINE | ID: mdl-26237909

RESUMO

INTRODUCTION: The incidence of Creutzfeldt-Jakob disease (CJD) in Finland in 1974-1989 was reported to be 0.6/1 000 000. Our aim was to compare the current incidence of CJD in Finland with the earlier incidence and also study the diagnostics of the disease. METHODS: Register study of the Finnish CJD cases from 1997 to 2012 and the clinical data of CJD patients within the Hospital District of Southwest Finland from 2007 to 2013. RESULTS: There were 119 cases. The average yearly incidence was 1.36-1.44/1 000 000. CONCLUSIONS: Compared with the previous study, the incidence in Finland appears to have increased. The change is propably due to increased awareness and improved diagnostic methods.


Assuntos
Síndrome de Creutzfeldt-Jakob/epidemiologia , Feminino , Finlândia/epidemiologia , Humanos , Incidência , Masculino , Fenótipo
19.
Hum Mol Genet ; 21(1): 66-75, 2012 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-21937588

RESUMO

Autosomal-inherited progressive external ophthalmoplegia (PEO) is an adult-onset disease characterized by the accumulation of multiple mitochondrial DNA (mtDNA) deletions in post-mitotic tissues. Mutations in six different genes have been described to cause the autosomal dominant form of the disease, but only mutations in the DNA polymerase gamma gene are known to cause autosomal recessive PEO (arPEO), leaving the genetic background of arPEO mostly unknown. Here we used whole-exome sequencing and identified compound heterozygous mutations, leading to two amino acid alterations R225W and a novel T230A in thymidine kinase 2 (TK2) in arPEO patients. TK2 is an enzyme of the mitochondrial nucleotide salvage pathway and its loss-of-function mutations have previously been shown to underlie the early-infantile myopathic form of mtDNA depletion syndrome (MDS). Our TK2 activity measurements of patient fibroblasts and mutant recombinant proteins show that the combination of the identified arPEO variants, R225W and T230A, leads to a significant reduction in TK2 activity, consistent with the late-onset phenotype, whereas homozygosity for R225W, previously associated with MDS, leads to near-total loss of activity. Our finding identifies a new genetic cause of arPEO with multiple mtDNA deletions. Furthermore, MDS and multiple mtDNA deletion disorders are manifestations of the same pathogenic pathways affecting mtDNA replication and repair, indicating that MDS-associated genes should be studied when searching for genetic background of PEO disorders.


Assuntos
DNA Mitocondrial/genética , Mitocôndrias/enzimologia , Mutação , Oftalmoplegia Externa Progressiva Crônica/enzimologia , Deleção de Sequência , Timidina Quinase/genética , Adulto , Sequência de Aminoácidos , Sequência de Bases , Replicação do DNA , DNA Mitocondrial/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Mitocôndrias/química , Dados de Sequência Molecular , Oftalmoplegia Externa Progressiva Crônica/genética , Alinhamento de Sequência , Timidina Quinase/química , Timidina Quinase/metabolismo
20.
Hum Mol Genet ; 21(20): 4521-9, 2012 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-22833457

RESUMO

Next-generation sequencing has turned out to be a powerful tool to uncover genetic basis of childhood mitochondrial disorders. We utilized whole-exome analysis and discovered novel compound heterozygous mutations in FARS2 (mitochondrial phenylalanyl transfer RNA synthetase), encoding the mitochondrial phenylalanyl transfer RNA (tRNA) synthetase (mtPheRS) in two patients with fatal epileptic mitochondrial encephalopathy. The mutations affected highly conserved amino acids, p.I329T and p.D391V. Recently, a homozygous FARS2 variant p.Y144C was reported in a Saudi girl with mitochondrial encephalopathy, but the pathogenic role of the variant remained open. Clinical features, including postnatal onset, catastrophic epilepsy, lactic acidemia, early lethality and neuroimaging findings of the patients with FARS2 variants, resembled each other closely, and neuropathology was consistent with Alpers syndrome. Our structural analysis of mtPheRS predicted that p.I329T weakened ATP binding in the aminoacylation domain, and in vitro studies with recombinant mutant protein showed decreased affinity of this variant to ATP. Furthermore, p.D391V and p.Y144C were predicted to disrupt synthetase function by interrupting the rotation of the tRNA anticodon stem-binding domain from a closed to an open form. In vitro characterization indicated reduced affinity of p.D391V mutant protein to phenylalanine, whereas p.Y144C disrupted tRNA binding. The stability of p.I329T and p.D391V mutants in a refolding assay was impaired. Our results imply that the three FARS2 mutations directly impair aminoacylation function and stability of mtPheRS, leading to a decrease in overall tRNA charging capacity. This study establishes a new genetic cause of infantile mitochondrial Alpers encephalopathy and reports a new mitochondrial aminoacyl-tRNA synthetase as a cause of mitochondrial disease.


Assuntos
Esclerose Cerebral Difusa de Schilder/genética , Mitocôndrias/enzimologia , Doenças Mitocondriais/genética , Proteínas Mitocondriais/genética , Fenilalanina-tRNA Ligase/genética , Sequência de Aminoácidos , Anticódon/metabolismo , Sequência de Bases , Esclerose Cerebral Difusa de Schilder/enzimologia , Esclerose Cerebral Difusa de Schilder/metabolismo , Exoma , Feminino , Humanos , Lactente , Mitocôndrias/metabolismo , Doenças Mitocondriais/enzimologia , Doenças Mitocondriais/metabolismo , Proteínas Mitocondriais/química , Proteínas Mitocondriais/metabolismo , Dados de Sequência Molecular , Mutação , Fenilalanina-tRNA Ligase/química , Fenilalanina-tRNA Ligase/metabolismo , Dobramento de Proteína , RNA de Transferência/genética , RNA de Transferência/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA