Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 79
Filtrar
1.
Am J Hum Genet ; 110(7): 1086-1097, 2023 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-37339631

RESUMO

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons. Although repeat expansion in C9orf72 is its most common cause, the pathogenesis of ALS isn't fully clear. In this study, we show that repeat expansion in LRP12, a causative variant of oculopharyngodistal myopathy type 1 (OPDM1), is a cause of ALS. We identify CGG repeat expansion in LRP12 in five families and two simplex individuals. These ALS individuals (LRP12-ALS) have 61-100 repeats, which contrasts with most OPDM individuals with repeat expansion in LRP12 (LRP12-OPDM), who have 100-200 repeats. Phosphorylated TDP-43 is present in the cytoplasm of iPS cell-derived motor neurons (iPSMNs) in LRP12-ALS, a finding that reproduces the pathological hallmark of ALS. RNA foci are more prominent in muscle and iPSMNs in LRP12-ALS than in LRP12-OPDM. Muscleblind-like 1 aggregates are observed only in OPDM muscle. In conclusion, CGG repeat expansions in LRP12 cause ALS and OPDM, depending on the length of the repeat. Our findings provide insight into the repeat length-dependent switching of phenotypes.


Assuntos
Esclerose Lateral Amiotrófica , Distrofias Musculares , Doenças Neurodegenerativas , Humanos , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Neurônios Motores/patologia , Distrofias Musculares/genética , Doenças Neurodegenerativas/genética , Proteína C9orf72/genética , Expansão das Repetições de DNA , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética
2.
Artigo em Inglês | MEDLINE | ID: mdl-38816190

RESUMO

BACKGROUND: Although pure GAA expansion is considered pathogenic in SCA27B, non-GAA repeat motif is mostly mixed into longer repeat sequences. This study aimed to unravel the complete sequencing of FGF14 repeat expansion to elucidate its repeat motifs and pathogenicity. METHODS: We screened FGF14 repeat expansion in a Japanese cohort of 460 molecularly undiagnosed adult-onset cerebellar ataxia patients and 1022 controls, together with 92 non-Japanese controls, and performed nanopore sequencing of FGF14 repeat expansion. RESULTS: In the Japanese population, the GCA motif was predominantly observed as the non-GAA motif, whereas the GGA motif was frequently detected in non-Japanese controls. The 5'-common flanking variant was observed in all Japanese GAA repeat alleles within normal length, demonstrating its meiotic stability against repeat expansion. In both patients and controls, pure GAA repeat was up to 400 units in length, whereas non-pathogenic GAA-GCA repeat was larger, up to 900 units, but they evolved from different haplotypes, as rs534066520, located just upstream of the repeat sequence, completely discriminated them. Both (GAA)≥250 and (GAA)≥200 were enriched in patients, whereas (GAA-GCA)≥200 was similarly observed in patients and controls, suggesting the pathogenic threshold of (GAA)≥200 for cerebellar ataxia. We identified 14 patients with SCA27B (3.0%), but their single-nucleotide polymorphism genotype indicated different founder alleles between Japanese and Caucasians. The low prevalence of SCA27B in Japanese may be due to the lower allele frequency of (GAA)≥250 in the Japanese population than in Caucasians (0.15% vs 0.32%-1.26%). CONCLUSIONS: FGF14 repeat expansion has unique features of pathogenicity and allelic origin, as revealed by a single ethnic study.

3.
Neuropathology ; 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38715398

RESUMO

A 68-year-old woman presented with difficulty finding words and writing characters. Neurological examination led to clinical diagnosis at onset of the logopenic variant of primary progressive aphasia accompanied with ideomotor apraxia, visuospatial agnosia on the right, and Gerstmann syndrome. Bradykinesia and rigidity on the right with shuffling gait developed after one year. Treatment with L-dopa had no effect. The patient was diagnosed with corticobasal syndrome (CBS). Brain magnetic resonance imaging revealed diffuse cortical atrophy dominantly on the left, especially in the temporal, parietal, and occipital lobes. Positron emission tomography did not reveal any significant accumulation of amyloid ß or tau protein. She died five years later. Neuropathological examination revealed diffuse cortical atrophy with severe neuronal loss and fibrous gliosis in the cortex. Neuronal cytoplasmic inclusions, short dystrophic neurites, and, most notably, neuronal intranuclear inclusions, all immunoreactive for phosphorylated TDP-43, were observed. Western blotting revealed a full length and fragments of phosphorylated TDP-43 at 45 and 23 kDa, respectively, confirming the pathological diagnosis of type A FTLD-TDP. Whole exome sequencing revealed a pathogenic mutation in GRN (c.87dupC). FTLD-TDP should be included in the differential diagnosis of CBS.

4.
Biochem Biophys Res Commun ; 683: 149106, 2023 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-37857162

RESUMO

Apolipoprotein E4 (APOE4), the strongest risk factor for late-onset Alzheimer's disease (AD), has been revealed to cause greater accumulation of extracellular amyloid ß (Aß) aggregates than does APOE3 in traditional transgenic mouse models of AD. However, concerns that the overexpression paradigm might have affected the phenotype remain. Amyloid precursor protein (APP)-knock-in (KI) mice, incorporating APP mutations associated with AD development, offer an alternative approach for overproducing pathogenic Aß without needing overexpression of APP. Here, we present the results of comprehensive analyses of pathological and biochemical traits in the brains of APP-KI mice harboring APP-associated familial AD mutations (APPNL-G-F/NL-G-F mice) crossed with human APOE-KI mice. Immunohistochemical and biochemical analyses revealed the APOE genotype-dependent increase in Aß pathology and glial activation, which was evident within 8 months in the mouse model. These results suggested that this mouse model may be valuable for investigating APOE pathobiology within a reasonable experimental time frame. Thus, this model can be considered in investigating the interaction between APOE and Aß in vivo, which may not be addressed appropriately by using other transgenic mouse models.


Assuntos
Doença de Alzheimer , Camundongos , Humanos , Animais , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Apolipoproteínas E/genética , Camundongos Transgênicos , Apolipoproteína E3/genética , Genótipo , Modelos Animais de Doenças
5.
J Hum Genet ; 68(2): 91-95, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36336708

RESUMO

Facioscapulohumeral dystrophy type1 (FSHD1) patients with a shortened D4Z4 repeat containing the DUX4 gene have a broad spectrum of clinical manifestations. In addition, high expression of DUX4 protein with an aberrant C terminus is frequently identified in B cell acute lymphoblastic leukemia. We investigated clinical manifestations in 31 FSHD1 patients and 30 non-affected individuals. Gastrointestinal cancers (gastric and colorectal cancers) increased after the age of 40 years and were more frequently observed in FSHD1 patients (n = 10) than in non-affected individuals (n = 2, p = 0.0217), though the incidence of cancers occurring in non-gastrointestinal tissues of FSHD1 patients was the same as that of non-affected individuals (p > 0.999). These comorbidities of FSHD1 patients were not associated with D4Z4 repeat number. Our results suggest that gastrointestinal cancers are among the extramuscular manifestations of adult FSHD1 patients, and do not depend on D4Z4 repeat number.


Assuntos
Neoplasias Gastrointestinais , Distrofia Muscular Facioescapuloumeral , Adulto , Humanos , Proteínas Cromossômicas não Histona/genética , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Distrofia Muscular Facioescapuloumeral/epidemiologia , Distrofia Muscular Facioescapuloumeral/genética , Distrofia Muscular Facioescapuloumeral/metabolismo , Neoplasias Gastrointestinais/epidemiologia , Neoplasias Gastrointestinais/genética
6.
Differentiation ; 123: 1-8, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34844057

RESUMO

Mutations in optineurin (OPTN) have been identified in a small proportion of sporadic and familial amyotrophic lateral sclerosis (ALS) cases. Recent evidences suggest that OPTN would be involved in not only the pathophysiological mechanisms of motor neuron death of ALS but also myofiber degeneration of sporadic inclusion body myositis. However, the detailed role of OPTN in muscle remains unclear. Initially, we showed that OPTN expression levels were significantly increased in the denervated muscles of mice, suggesting that OPTN may be involved in muscle homeostasis. To reveal the molecular role of OPTN in muscle atrophy, we used cultured C2C12 myotubes treated with tumor necrosis factor-like inducer of apoptosis (TWEAK) as an in vitro model of muscle atrophy. Our data showed that OPTN had no effect on the process of muscle atrophy in this model. On the other hand, we found that myogenic differentiation was affected by OPTN. Immunoblotting analysis showed that OPTN protein levels gradually decreased during C2C12 differentiation. Furthermore, OPTN knockdown inhibited C2C12 differentiation, accompanied by reduction of mRNA and protein expression levels of myogenin and MyoD. These findings suggested that OPTN may have a novel function in muscle homeostasis and play a role in the pathogenesis of neuromuscular diseases.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Animais , Diferenciação Celular/genética , Camundongos , Atrofia Muscular/patologia , Proteína MyoD/genética , Mioblastos/metabolismo , Miogenina/genética , Fator de Transcrição TFIIIA/genética , Fator de Transcrição TFIIIA/metabolismo
7.
J Physiol ; 599(2): 547-569, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33151574

RESUMO

KEY POINTS: Some ion channels are known to behave as inductors and make up the parallel resonant circuit in the plasma membrane of neurons, which enables neurons to respond to current inputs with a specific frequency (so-called 'resonant properties'). Here, we report that heterologous expression of mouse Kv11 voltage-dependent K+ channels generate resonance and oscillation at depolarized membrane potentials in HEK293 cells; expressions of individual Kv11 subtypes generate resonance and oscillation with different frequency properties. Kv11.3-expressing HEK293 cells exhibited transient conductance changes that opposed the current changes induced by voltage steps; this probably enables Kv11 channels to behave like an inductor. The resonance and oscillation of inferior olivary neurons were impaired at the resting membrane potential in Kv11.3 knockout mice. This study helps to elucidate basic ion channel properties that are crucial for the frequency responses of neurons. ABSTRACT: The plasma membranes of some neurons preferentially respond to current inputs with a specific frequency, and output as large voltage changes. This property is called resonance, and is thought to be mediated by ion channels that show inductor-like behaviour. However, details of the candidate ion channels remain unclear. In this study, we mainly focused on the functional roles of Kv11 potassium (K+ ) channels, encoded by ether-á-go-go-related genes, in resonance in mouse inferior olivary (IO) neurons. We transfected HEK293 cells with long or short splice variants of Kv11.1 (Merg1a and Merg1b) or Kv11.3, and examined membrane properties using whole-cell recording. Transfection with Kv11 channels reproduced resonance at membrane potentials depolarized from the resting state. Frequency ranges of Kv11.3-, Kv11.1(Merg1b)- and Kv11.1(Merg1a)-expressing cells were 2-6 Hz, 2-4 Hz, and 0.6-0.8 Hz, respectively. Responses of Kv11.3 currents to step voltage changes were essentially similar to those of inductor currents in the resistor-inductor-capacitor circuit. Furthermore, Kv11 transfections generated membrane potential oscillations. We also confirmed the contribution of HCN1 channels as a major mediator of resonance at more hyperpolarized potentials by transfection into HEK293 cells. The Kv11 current kinetics and properties of Kv11-dependent resonance suggested that Kv11.3 mediated resonance in IO neurons. This finding was confirmed by the impairment of resonance and oscillation at -30 to -60 mV in Kcnh7 (Kv11.3) knockout mice. These results suggest that Kv11 channels have important roles in inducing frequency-dependent responses in a subtype-dependent manner from resting to depolarized membrane potentials.


Assuntos
Éter , Potássio , Animais , Células HEK293 , Humanos , Potenciais da Membrana , Camundongos , Técnicas de Patch-Clamp
8.
Neurobiol Dis ; 148: 105215, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33296728

RESUMO

We previously showed that optineurin (OPTN) mutations lead to the development of amyotrophic lateral sclerosis. The association between OPTN mutations and the pathogenesis of amyotrophic lateral sclerosis remains unclear. To investigate the mechanism underlying its pathogenesis, we generated Optn knockout mice. We evaluated histopathological observations of these mice and compared with those of OPTN- amyotrophic lateral sclerosis cases to investigate the mechanism underlying the pathogenesis of amyotrophic lateral sclerosis caused by OPTN mutations. The Optn (-/-) mice presented neuronal autophagic vacuoles immunopositive for charged multivesicular body protein 2b, one of the hallmarks of granulovacuolar degenerations, in the cytoplasm of spinal cord motor neurons at the age of 8 months and the OPTN- amyotrophic lateral sclerosis case with homozygous Q398X mutation. In addition, Optn (-/-) mice showed TAR-DNA binding protein 43/sequestosome1/p62 -positive cytoplasmic inclusions and the clearance of nuclear TAR-DNA binding protein 43. The axonal degeneration of the sciatic nerves was observed in Optn (-/-) mice. However, we could not observe significant differences in survival time, body weight, and motor functions, at 24 months. Our findings suggest that homozygous OPTN deletion or mutations might result in autophagic dysfunction and TAR-DNA binding protein 43 mislocalization, thereby leading to neurodegeneration of motor neurons. These findings indicate that the Optn (-/-) mice recapitulate both common and specific pathogenesis of amyotrophic lateral sclerosis associated with autophagic abnormalities. Optn (-/-) mice could serve as a mouse model for the development of therapeutic strategies.


Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Autofagia/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/metabolismo , Hipocampo/metabolismo , Proteínas de Membrana Transportadoras/genética , Neocórtex/metabolismo , Medula Espinal/metabolismo , Vacúolos/metabolismo , Idoso de 80 Anos ou mais , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Esclerose Lateral Amiotrófica/fisiopatologia , Animais , Hipocampo/patologia , Humanos , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Corpos Multivesiculares/metabolismo , Neocórtex/patologia , Medula Espinal/patologia , Vacúolos/patologia
9.
J Hum Genet ; 66(10): 957-964, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33742109

RESUMO

Parkinson's disease (PD) is caused by a combination of genetic and environmental factors. Notably, genetic risk factors vary according to ethnicity and geographical regions, and few studies have analyzed the frequency of PD causative genes in Japanese patients. Therefore, we performed genetic analyses of Japanese patients with PD. We recruited 221 participants, including 26 patients with familial PD. Genetic risk factors were evaluated by target sequencing and gene dosage analysis. We detected the genetic risk factors in 58 cases (26.2%) and classified patients into three groups to clarify the differences in genetic risk factors by age at onset (AAO). The early-onset group (AAO < 50 years) included 18 cases (44.7%), who tended to have a larger number of genetic risk factors than the later-onset groups. Regarding the AAO for each causative gene, patients with PRKN variants were significantly younger at onset than those bearing LRRK2 variants. LRRK2 variants showed similar frequency in each AAO group. Of note, we identified two novel variants. Patients with early-onset PD have more genetic risk factors than patients with late-onset PD. In Japanese patients with PD, PRKN, and LRRK2 were the major PD-related genes. Particularly, LRRK2 was a common genetic factor in all age groups because of the presence of the Asian-specific variant such as LRRK2 p.G2385R. Accumulation of genetic and clinical data can contribute to the development of treatments for PD.


Assuntos
Predisposição Genética para Doença , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Doença de Parkinson/genética , Adulto , Idade de Início , Povo Asiático/genética , Feminino , Testes Genéticos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/epidemiologia , Doença de Parkinson/patologia , Fatores de Risco
10.
BMC Neurol ; 21(1): 396, 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34641814

RESUMO

BACKGROUND: Both fragile X-associated tremor/ataxia syndrome (FXTAS) and late-onset neuronal intranuclear inclusion disease (NIID) show CGG/GGC trinucleotide repeat expansions. Differentiating these diseases are difficult because of the similarity in their clinical and radiological features. It is unclear that skin biopsy can distinguish NIID from FXTAS. We performed a skin biopsy in an FXTAS case with cognitive dysfunction and peripheral neuropathy without tremor, which was initially suspected to be NIID. CASE PRESENTATION: The patient underwent neurological assessment and examinations, including laboratory tests, electrophysiologic test, imaging, skin biopsy, and genetic test. A brain MRI showed hyperintensity lesions along the corticomedullary junction on diffusion-weighted imaging (DWI) in addition to middle cerebellar peduncle sign (MCP sign). We suspected NIID from the clinical picture and the radiological findings, and performed a skin biopsy. The skin biopsy specimen showed ubiquitin- and p62-positive intranuclear inclusions, suggesting NIID. However, a genetic analysis for NIID using repeat-primed polymerase chain reaction (RP-PCR) revealed no expansion detected in the Notch 2 N-terminal like C (NOTCH2NLC) gene. We then performed genetic analysis for FXTAS using RP-PCR, which revealed a repeat CGG/GGC expansion in the FMRP translational regulator 1 (FMR1) gene. The number of repeats was 83. We finally diagnosed the patient with FXTAS rather than NIID. CONCLUSIONS: For the differential diagnosis of FXTAS and NIID, a skin biopsy alone is insufficient; instead, genetic analysis, is essential. Further investigations in additional cases based on genetic analysis are needed to elucidate the clinical and pathological differences between FXTAS and NIID.


Assuntos
Corpos de Inclusão Intranuclear , Tremor , Ataxia , Biópsia , Proteína do X Frágil da Deficiência Intelectual , Síndrome do Cromossomo X Frágil , Humanos , Doenças Neurodegenerativas
11.
Epilepsy Behav ; 117: 107886, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33714184

RESUMO

OBJECTIVE: To identify people with epilepsy (PWE) who required extensive care before the novel coronavirus disease 2019 (COVID-19) pandemic that had world-wide impacts on medical care and on socio-economic conditions. METHODS: Consecutive PWE who were treated at the epilepsy center of Hiroshima University Hospital, which was located in the COVID-19 non-pandemic area, between March 2019 and August 2020 were enrolled. We evaluated clinical and socioeconomic factors that were associated with seizure exacerbation (an increase in seizure frequency) during the first 6 months after the COVID-19 pandemic started compared with the previous 6 months. RESULTS: Among the 196 PWE who were evaluated (mean age was 37.8 ±â€¯16.2 years), there were 33 PWE (16.8%) whose seizure frequency had increased after the pandemic began. People with epilepsy with a seizure increase showed a significant association with living alone (p < 0.001), a higher seizure frequency (p < 0.001), negative findings on MRI (p = 0.020), history of dissociative seizure (p < 0.001), mood disorders (p < 0.001), insomnia (p < 0.001), and high psychological stress levels (p = 0.024) at baseline compared with PWE without seizure exacerbation. Multivariate logistic regression analysis revealed that "living alone" (odds ratio (OR) 3.69; 95%CI 1.29-10.52), "high seizure frequency at baseline" (OR 4.53; 95%CI 1.63-12.57), and "comorbidity of insomnia" (OR 9.55; 95%CI 3.71-24.55) were independently associated with seizure exacerbation. CONCLUSIONS: Even in the non-pandemic area, PWE had seizure exacerbation, suggesting that clinicians should screen patients' mental health before the outbreak to provide care, reduce the burden, and prevent social isolation in PWE. This should be addressed particularly in patients with medically refractory seizures with insomnia who live alone.


Assuntos
COVID-19 , Epilepsia , Adulto , Epilepsia/epidemiologia , Humanos , Pessoa de Meia-Idade , Pandemias , SARS-CoV-2 , Fatores Socioeconômicos , Adulto Jovem
12.
Neuropathology ; 41(2): 118-126, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33415820

RESUMO

We here report an autopsy case of familial amyotrophic lateral sclerosis (ALS) with p.Arg487His mutation in the valosin-containing protein (VCP) gene (VCP), in which upper motor neurons (UMNs) were predominantly involved. Moreover, our patient developed symptoms of frontotemporal dementia later in life and pathologically exhibited numerous phosphorylated transactivation response DNA-binding protein of 43 kDa (p-TDP-43)-positive neuronal cytoplasmic inclusions and short dystrophic neurites with a few lentiform neuronal intranuclear inclusions, sharing the features of frontotemporal lobar degeneration with TDP-43 pathology type A pattern. A review of previous reports of ALS with VCP mutations suggests that our case is unique in terms of its UMN-predominant lesion pattern and distribution of p-TDP-43 pathology. Thus, this case report effectively expands the clinical and pathological phenotype of ALS in patients with a VCP mutation.


Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Autopsia , Mutação/genética , Proteinopatias TDP-43/metabolismo , Proteína com Valosina/genética , Autopsia/métodos , Proteínas de Ligação a DNA/metabolismo , Degeneração Lobar Frontotemporal/metabolismo , Degeneração Lobar Frontotemporal/patologia , Humanos , Corpos de Inclusão Intranuclear/metabolismo , Masculino , Pessoa de Meia-Idade , Neurônios Motores/patologia , Proteína com Valosina/metabolismo
13.
Biochem Biophys Res Commun ; 525(4): 889-894, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32171527

RESUMO

A sophisticated and delicate balance between bone resorption by osteoclasts and bone formation by osteoblasts regulates bone metabolism. Optineurin (OPTN) is a gene involved in primary open-angle glaucoma and amyotrophic lateral sclerosis. Although its function has been widely studied in ophthalmology and neurology, recent reports have shown its possible involvement in bone metabolism through negative regulation of osteoclast differentiation. However, little is known about the role of OPTN in osteoblast function. Here, we demonstrated that OPTN controls not only osteoclast but also osteoblast differentiation. Different parameters involved in osteoblastogenesis and osteoclastogenesis were assessed in Optn-/- mice. The results showed that osteoblasts from Optn-/- mice had impaired alkaline phosphatase activity, defective mineralized nodules, and inability to support osteoclast differentiation. Moreover, OPTN could bind to signal transducer and activator of transcription 1 (STAT1) and regulate runt-related transcription factor 2 (RUNX2) nuclear localization by modulating STAT1 levels in osteoblasts. These data suggest that OPTN is involved in bone metabolism not only by regulating osteoclast function but also by regulating osteoblast function by mediating RUNX2 nuclear translocation via STAT1.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Osteoblastos/citologia , Osteogênese/fisiologia , Fator de Transcrição STAT1/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Diferenciação Celular/fisiologia , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Proteínas de Membrana Transportadoras/genética , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Osteoclastos/citologia , Osteoclastos/metabolismo
14.
BMC Med Genet ; 21(1): 68, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-32234020

RESUMO

BACKGROUND: The TWNK gene encodes the twinkle protein, which is a mitochondrial helicase for DNA replication. The dominant TWNK variants cause progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, while the recessive variants cause mitochondrial DNA depletion syndrome 7 and Perrault syndrome 5. Perrault syndrome is characterized by sensorineural hearing loss in both males and females and gonadal dysfunction in females. Patients with Perrault syndrome may present early-onset cerebellar ataxia, whereas middle-age-onset cerebellar ataxia caused by TWNK variants is rare. CASE PRESENTATION: A Japanese female born to consanguineous parents presented hearing loss at age 48, a staggering gait at age 53, and numbness in her distal extremities at age 57. Neurological examination revealed sensorineural hearing loss, cerebellar ataxia, decreased deep tendon reflexes, and sensory disturbance in the distal extremities. Laboratory tests showed no abnormal findings other than a moderate elevation of pyruvate concentration levels. Brain magnetic resonance imaging revealed mild cerebellar atrophy. Using exome sequencing, we identified a homozygous TWNK variant (NM_021830: c.1358G>A, p.R453Q). CONCLUSIONS: TWNK variants could cause middle-age-onset cerebellar ataxia. Screening for TWNK variants should be considered in cases of cerebellar ataxia associated with deafness and/or peripheral neuropathy, even if the onset is not early.


Assuntos
Ataxia Cerebelar/genética , DNA Helicases/genética , Proteínas Mitocondriais/genética , Ataxia Cerebelar/complicações , Ataxia Cerebelar/diagnóstico , Consanguinidade , Feminino , Marcha Atáxica/complicações , Marcha Atáxica/diagnóstico , Marcha Atáxica/genética , Disgenesia Gonadal 46 XX/diagnóstico , Disgenesia Gonadal 46 XX/genética , Perda Auditiva/complicações , Perda Auditiva/diagnóstico , Perda Auditiva/genética , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/genética , Homozigoto , Humanos , Japão , Transtornos de Início Tardio/diagnóstico , Transtornos de Início Tardio/genética , Pessoa de Meia-Idade , Mutação , Linhagem
15.
J Hum Genet ; 65(10): 917-920, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32451491

RESUMO

Primary familial brain calcification (PFBC) is a hereditary neurological disorder characterized by idiopathic calcification of the bilateral basal ganglia and other areas of the brain. MYORG has been identified as the first causative gene of autosomal recessive PFBC in Chinese families. There have been several reports of PFBC associated with MYORG (MYORG-PFBC) in individuals of Middle Eastern, European, and Latin American ancestry but to date, there have been no reported Japanese cases. We report the first Japanese case of MYORG-PFBC. The patient was a 43-year-old Japanese woman who experienced mild headaches and cerebellar ataxia including dysarthria. Computed tomography showed calcification in the cerebral white matter, basal ganglia, cerebellum, and brainstem. Using exome sequencing, we identified a homozygous variant in the MYORG gene (NM_020702.4: c.794C>T,p.Thr265Met). Our patient presented dysarthria and extensive calcification affecting the pons, which are specific features of MYORG-PFBC. We report clinical symptoms and imaging findings of a case with p.Thr265Met variant.


Assuntos
Encefalopatias/genética , Calcinose/genética , Glicosídeo Hidrolases/genética , Mutação de Sentido Incorreto , Mutação Puntual , Adulto , Substituição de Aminoácidos , Povo Asiático/genética , Encefalopatias/diagnóstico por imagem , Encefalopatias/patologia , Calcinose/diagnóstico por imagem , Calcinose/patologia , Ataxia Cerebelar/genética , Consanguinidade , Disartria/genética , Feminino , Glicosídeo Hidrolases/química , Cefaleia/genética , Homozigoto , Humanos , Japão , Linhagem , Sequenciamento do Exoma
16.
J Hum Genet ; 65(4): 363-369, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31907387

RESUMO

Spinocerebellar ataxia (SCA) is a genetically heterogeneous disease characterized by cerebellar ataxia. Many causative genes have been identified to date, the most common etiology being the abnormal expansion of repeat sequences, and the mutation of ion channel genes also play an important role in the development of SCA. Some of them encode calcium and potassium channels. However, due to limited reports about potassium genes in SCA, we screened 192 Japanese individuals with dominantly inherited SCA who had no abnormal repeat expansions of causative genes for potassium channel mutations (KCNC3 for SCA13 and KCND3 for SCA19/SCA22) by target sequencing. As a result, two variants were identified from two patients: c.1973G>A, p.R658Q and c.1018G>A, p.V340M for KCNC3, and no pathogenic variant was identified for KCND3. The newly identified p.V340M exists in the extracellular domain, and p.R658Q exists in the intracellular domain on the C-terminal side, although most of the reported KCNC3 mutations are present at the transmembrane site. Adult-onset and slowly progressive cerebellar ataxia are the main clinical features of SCA13 and SCA19 caused by potassium channel mutations, which was similar in our cases. SCA13 caused by KCNC3 mutations may present with deep sensory loss and cognitive impairment in addition to cerebellar ataxia. In this study, mild deep sensory loss was observed in one case. SCA caused by potassium channel gene mutations is extremely rare, and more cases should be accumulated in the future to elucidate its pathogenesis due to channel dysfunction.


Assuntos
Disfunção Cognitiva/genética , Mutação , Canais de Potássio/genética , Ataxias Espinocerebelares/genética , Adulto , Povo Asiático , Disfunção Cognitiva/diagnóstico por imagem , Feminino , Testes Genéticos , Humanos , Japão , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Ataxias Espinocerebelares/diagnóstico por imagem
17.
J Hum Genet ; 65(10): 841-846, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32424308

RESUMO

Aggressive periodontitis (AgP) occurs at an early age and causes rapid periodontal tissue destruction. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) encodes a protein with two caspase recruitment domains and eleven leucine-rich repeats. This protein is expressed mainly in peripheral blood leukocytes and is involved in immune response. NOD2 variants have been associated with increased susceptibility to Crohn's disease, and recently, NOD2 was reported as a causative gene in AgP. The present study aimed to identify potential NOD2 variants in an AgP cohort (a total of 101 patiens: 37 patients with positive family histories and 64 sporadic patients). In the familial group, six patients from two families had a reported heterozygous missense variant (c.C931T, p.R311W). Four patients in the sporadic group had a heterozygous missense variant (c.C1411T, p.R471C), with no reported association to the disease. Overall, two NOD2 variants, were identified in 10% of our AgP cohort. These variants were different from the major variants reported in Crohn's disease. More cases need to be investigated to elucidate the role of NOD2 variants in AgP pathology.


Assuntos
Periodontite Agressiva/genética , Mutação de Sentido Incorreto , Proteína Adaptadora de Sinalização NOD2/genética , Adulto , Periodontite Agressiva/diagnóstico por imagem , Periodontite Agressiva/imunologia , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Masculino , Proteína Adaptadora de Sinalização NOD2/química , Linhagem , Domínios Proteicos
18.
Hum Mol Genet ; 26(22): 4429-4440, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-28973348

RESUMO

Primary microcephaly (MCPH) is an autosomal recessive disorder characterized by congenital reduction of head circumference. Here, we identified compound heterozygous mutations c.731 C > T (p.Ser 244 Leu) and c.2413 G > T (p.Glu 805 X) in the WDR62/MCPH2 gene, which encodes the mitotic centrosomal protein WDR62, in two siblings in a Japanese family with microcephaly using whole-exome sequencing. However, the molecular and cellular pathology of microcephaly caused by WDR62/MCPH2 mutation remains unclear. To clarify the physiological role of WDR62, we used the CRISPR/Cas9 system and single-stranded oligonucleotides as a point-mutation-targeting donor to generate human cell lines with knock-in of WDR62/MCPH2 c.731 C > T (p.Ser 244 Leu) missense mutation. In normal metaphase, the mitotic spindle forms parallel to the substratum to ensure symmetric cell division, while WDR62/MCPH2-mutated cells exhibited a randomized spindle orientation caused by the impaired astral microtubule assembly. It was shown that a mitotic kinase, Polo-like kinase 1 (PLK1), is required for the maintenance of spindle orientation through astral microtubule development. In this study, we demonstrated that WDR62 is a PLK1 substrate that is phosphorylated at Ser 897, and that this phosphorylation at the spindle poles promotes astral microtubule assembly to stabilize spindle orientation. Our findings provide insights into the role of the PLK1-WDR62 pathway in the maintenance of proper spindle orientation.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Fuso Acromático/fisiologia , Sequência de Bases , Proteínas de Ciclo Celular/genética , Divisão Celular/genética , Linhagem Celular , Centrossomo/metabolismo , Feminino , Técnicas de Introdução de Genes , Células HCT116 , Humanos , Recém-Nascido , Masculino , Microcefalia/genética , Microcefalia/metabolismo , Microtúbulos/genética , Microtúbulos/metabolismo , Mitose/genética , Mitose/fisiologia , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/genética , Fosforilação , Gravidez , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Fuso Acromático/genética , Fuso Acromático/metabolismo , Quinase 1 Polo-Like
19.
BMC Neurol ; 19(1): 168, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31319800

RESUMO

BACKGROUND: The coexistence of distinct neurodegenerative diseases in single cases has recently attracted greater attention. The phenotypic co-occurrence of progressive supranuclear palsy (PSP) and amyotrophic lateral sclerosis (ALS) has been documented in several cases. That said, the clinicopathological comorbidity of these two diseases has not been demonstrated. CASE PRESENTATION: A 77-year-old man presented with gait disturbance for 2 years, consistent with PSP with progressive gait freezing. At 79 years old, he developed muscle weakness compatible with ALS. The disease duration was 5 years after the onset of PSP and 5 months after the onset of ALS. Neuropathological findings demonstrated the coexistence of PSP and ALS. Immunohistochemical examination confirmed 4-repeat tauopathy, including globose-type neurofibrillary tangles, tufted astrocytes, and oligodendroglial coiled bodies as well as TAR DNA-binding protein 43 kDa pathology in association with upper and lower motor neuron degeneration. Immunoblotting showed hyperphosphorylated full-length 4-repeat tau bands (64 and 68 kDa) and C-terminal fragments (33 kDa), supporting the diagnosis of PSP and excluding other parkinsonian disorders, such as corticobasal degeneration. Genetic studies showed no abnormalities in genes currently known to be related to ALS or PSP. CONCLUSIONS: Our case demonstrates the clinicopathological comorbidity of PSP and ALS in a sporadic patient. The possibility of multiple proteinopathies should be considered when distinct symptoms develop during the disease course.


Assuntos
Esclerose Lateral Amiotrófica/complicações , Encéfalo/patologia , Paralisia Supranuclear Progressiva/complicações , Idoso , Esclerose Lateral Amiotrófica/diagnóstico por imagem , Esclerose Lateral Amiotrófica/patologia , Astrócitos/patologia , Encéfalo/diagnóstico por imagem , Comorbidade , Proteínas de Ligação a DNA , Evolução Fatal , Humanos , Masculino , Transtornos dos Movimentos/etiologia , Emaranhados Neurofibrilares/patologia , Paralisia Supranuclear Progressiva/diagnóstico por imagem , Paralisia Supranuclear Progressiva/patologia , Proteínas tau/análise
20.
Neuropathology ; 39(1): 47-53, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30511354

RESUMO

Amyotrophic lateral sclerosis (ALS) primarily affects upper and lower motor neurons. Phosphorylated trans-activation response DNA-binding protein of 43 kDa (TDP-43) inclusion bodies are reportedly a pathological hallmark of sporadic ALS. Here, we present an atypical case of sporadic ALS that progressed very slowly, persisted for 19 years, and clinically appeared to only affect the lower motor neurons; however, upper motor neuron degeneration was detected at autopsy. Furthermore, no inclusion bodies positive for phosphorylated TDP-43, ubiquitin, fused in sarcoma, or superoxide dismutase-1 were detected in the central nervous system. We performed exome-sequencing data analysis but found no genetic disorders. This was therefore an unusual case of lower motor neuron-predominant ALS without TDP-43 pathology or known gene-disease associations. We also reviewed autopsied ALS cases that progressed slowly and had no phosphorylated TDP-43 or ubiquitin-positive inclusions and present the clinicopathological features of such cases. Based on these results, there may be a sporadic ALS subgroup that progresses slowly and shows no accumulation of phosphorylated TDP-43.


Assuntos
Esclerose Lateral Amiotrófica/patologia , Progressão da Doença , Atrofia Muscular Espinal/patologia , Esclerose Lateral Amiotrófica/complicações , Esclerose Lateral Amiotrófica/metabolismo , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Corpos de Inclusão/metabolismo , Pessoa de Meia-Idade , Atrofia Muscular Espinal/complicações , Atrofia Muscular Espinal/metabolismo
SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa