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1.
Hum Mol Genet ; 23(21): 5838-46, 2014 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-24899047

RESUMO

The triggering receptor expressed on myeloid 2 (TREM2) is an immune phagocytic receptor expressed on brain microglia known to trigger phagocytosis and regulate the inflammatory response. Homozygous mutations in TREM2 cause Nasu-Hakola disease, a rare recessive form of dementia. A heterozygous TREM2 variant, p.R47H, was recently shown to increase Alzheimer''s disease (AD) risk. We hypothesized that if TREM2 is truly an AD risk gene, there would be additional rare variants in TREM2 that substantially affect AD risk. To test this hypothesis, we performed pooled sequencing of TREM2 coding regions in 2082 AD cases and 1648 cognitively normal elderly controls of European American descent. We identified 16 non-synonymous variants, six of which were not identified in previous AD studies. Two variants, p.R47H [P = 9.17 × 10(-4), odds ratio (OR) = 2.63 (1.44-4.81)] and p.R62H [P = 2.36 × 10(-4), OR = 2.36 (1.47-3.80)] were significantly associated with disease risk in single-variant analyses. Gene-based tests demonstrate variants in TREM2 are genome-wide significantly associated with AD [PSKAT-O = 5.37 × 10(-7); OR = 2.55 (1.80-3.67)]. The association of TREM2 variants with AD is still highly significant after excluding p.R47H [PSKAT-O = 7.72 × 10(-5); OR = 2.47 (1.62-3.87)], indicating that additional TREM2 variants affect AD risk. Genotyping in available family members of probands suggested that p.R47H (P = 4.65 × 10(-2)) and p.R62H (P = 6.87 × 10(-3)) were more frequently seen in AD cases versus controls within these families. Gel electrophoresis analysis confirms that at least three TREM2 transcripts are expressed in human brains, including one encoding a soluble form of TREM2.


Assuntos
Doença de Alzheimer/genética , Variação Genética , Glicoproteínas de Membrana/genética , Fases de Leitura Aberta , Receptores Imunológicos/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Processamento Alternativo , Doença de Alzheimer/diagnóstico , Sequência de Aminoácidos , Encéfalo/metabolismo , Encéfalo/patologia , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Glicoproteínas de Membrana/química , Pessoa de Meia-Idade , Dados de Sequência Molecular , Polimorfismo de Nucleotídeo Único , Receptores Imunológicos/química , Risco , Alinhamento de Sequência
2.
J Alzheimers Dis ; 77(4): 1469-1482, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32894242

RESUMO

BACKGROUND: Rare variants in PLCG2 (p.P522R), ABI3 (p.S209F), and TREM2 (p.R47H, p.R62H) have been associated with late onset Alzheimer's disease (LOAD) risk in Caucasians. After the initial report, several studies have found positive results in cohorts of different ethnic background and with different phenotype. OBJECTIVE: In this study, we aim to evaluate the association of rare coding variants in PLCG2, ABI3, and TREM2 with LOAD risk and their effect at different time points of the disease. METHODS: We used a European American cohort to assess the association of the variants prior onset (using CSF Aß42, tau, and pTau levels, and amyloid imaging as endophenotypes) and after onset (measured as rate of memory decline). RESULTS: We confirm the association with LOAD risk of TREM2 p.R47H, p.R62H and ABI3 p.S209F variants, and the protective effect of PLCG2 p.P522R. In addition, ABI3 and TREM2 gene-sets showed significant association with LOAD risk. TREM2 p.R47H and PLCG2 p.P522R variants were also statistically associated with increase of amyloid imaging and AD progression, respectively. We did not observe any association of ABI3 p.S209F with any of the other AD endophenotypes. CONCLUSION: The results of this study highlight the importance of including biomarkers and alternative phenotypes to better understand the role of novel candidate genes with the disease.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Doença de Alzheimer/genética , Variação Genética/genética , Glicoproteínas de Membrana/genética , Fenótipo , Fosfolipase C gama/genética , Receptores Imunológicos/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Estudos de Coortes , Bases de Dados Genéticas/tendências , Feminino , Humanos , Masculino
3.
Ann Neurol ; 63(4): 535-8, 2008 04.
Artigo em Inglês | MEDLINE | ID: mdl-18288693

RESUMO

To identify novel causes of familial neurodegenerative diseases, we extended our previous studies of TAR DNA-binding protein 43 (TDP-43) proteinopathies to investigate TDP-43 as a candidate gene in familial cases of motor neuron disease. Sequencing of the TDP-43 gene led to the identification of a novel missense mutation, Ala-315-Thr, which segregates with all affected members of an autosomal dominant motor neuron disease family. The mutation was not found in 1,505 healthy control subjects. The discovery of a missense mutation in TDP-43 in a family with dominantly inherited motor neuron disease provides evidence of a direct link between altered TDP-43 function and neurodegeneration.


Assuntos
Substituição de Aminoácidos/genética , Proteínas de Ligação a DNA/genética , Doença dos Neurônios Motores/genética , Mutação de Sentido Incorreto/genética , Idoso , Idoso de 80 Anos ou mais , Alanina/genética , Sequência de Aminoácidos , Análise Mutacional de DNA , Feminino , Genes Dominantes , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Doença dos Neurônios Motores/metabolismo , Doença dos Neurônios Motores/patologia , Linhagem , Treonina/genética
4.
Alzheimers Res Ther ; 10(1): 67, 2018 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-30021643

RESUMO

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease that is clinically characterized by progressive cognitive decline. Mutations in amyloid-ß precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are the pathogenic cause of autosomal dominant AD (ADAD). However, polymorphisms also exist within these genes. METHODS: In order to distinguish polymorphisms from pathogenic mutations, the DIAN Expanded Registry has implemented an algorithm for determining ADAD pathogenicity using available information from multiple domains, including genetic, bioinformatic, clinical, imaging, and biofluid measures and in vitro analyses. RESULTS: We propose that PSEN1 M84V, PSEN1 A396T, PSEN2 R284G, and APP T719N are likely pathogenic mutations, whereas PSEN1 c.379_382delXXXXinsG and PSEN2 L238F have uncertain pathogenicity. CONCLUSIONS: In defining a subset of these variants as pathogenic, individuals from these families can now be enrolled in observational and clinical trials. This study outlines a critical approach for translating genetic data into meaningful clinical outcomes.


Assuntos
Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Mutação/genética , Presenilina-1/genética , Presenilina-2/genética , Algoritmos , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/metabolismo , Compostos de Anilina/metabolismo , Linhagem Celular Tumoral , Biologia Computacional , Análise Mutacional de DNA , Saúde da Família , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroblastoma/patologia , Fragmentos de Peptídeos/metabolismo , Tomografia por Emissão de Pósitrons , Reprodutibilidade dos Testes , Tiazóis/metabolismo , Transfecção
5.
Acta Neuropathol Commun ; 3: 73, 2015 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-26610600

RESUMO

Autosomal dominant adult-onset neuronal ceroid lipofuscinosis (AD-ANCL) is a multisystem disease caused by mutations in the DNAJC5 gene. DNAJC5 encodes Cysteine String Protein-alpha (CSPα), a putative synaptic protein. AD-ANCL has been traditionally considered a lysosomal storage disease based on the intracellular accumulation of ceroid material. Here, we report for the first time the pathological findings of a patient in a clinically early stage of disease, which exhibits the typical neuronal intracellular ceroid accumulation and incipient neuroinflammation but no signs of brain atrophy, neurodegeneration or massive synaptic loss. Interestingly, we found minimal or no apparent reductions in CSPα or synaptophysin in the neuropil. In contrast, brain homogenates from terminal AD-ANCL patients exhibit significant reductions in SNARE-complex forming presynaptic protein levels, including a significant reduction in CSPα and SNAP-25. Frozen samples for the biochemical analyses of synaptic proteins were not available for the early stage AD-ANLC patient. These results suggest that the degeneration seen in the patients with AD-ANCL reported here might be a consequence of both the early effects of CSPα mutations at the cellular soma, most likely lysosome function, and subsequent neuronal loss and synaptic dysfunction.


Assuntos
Encéfalo/patologia , Proteínas de Choque Térmico HSP40/genética , Proteínas de Membrana/genética , Mutação/genética , Lipofuscinoses Ceroides Neuronais/genética , Lipofuscinoses Ceroides Neuronais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/ultraestrutura , Análise Mutacional de DNA , Feminino , Regulação da Expressão Gênica/genética , Proteína Glial Fibrilar Ácida/metabolismo , Proteínas de Choque Térmico HSP40/metabolismo , Proteínas de Choque Térmico HSP40/ultraestrutura , Humanos , Masculino , Proteínas de Membrana/metabolismo , Proteínas de Membrana/ultraestrutura , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Neurônios/metabolismo , Neurônios/patologia , Neurônios/ultraestrutura , Sinaptofisina/metabolismo
6.
Arch Neurol ; 68(5): 581-6, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21220649

RESUMO

OBJECTIVE: To test whether rs1990622 (TMEM106B) is associated with age at onset (AAO) in granulin (GRN) mutation carriers and with plasma GRN levels in mutation carriers and healthy, elderly individuals. Rs1990622 (TMEM106B) was identified as a risk factor for frontotemporal lobar degeneration with TAR DNA-binding protein inclusions (FTLD-TDP) in a recent genome-wide association. DESIGN: Rs1990622 was genotyped in GRN mutation carriers and tested for association with AAO using the Kaplan-Meier method and a Cox proportional hazards model. SETTING: Alzheimer's Disease Research Center. Subjects  We analyzed 50 affected and unaffected GRN mutation carriers from 4 previously reported FTLD-TDP families (HDDD1, FD1, HDDD2, and the Karolinska family). The GRN plasma levels were also measured in 73 healthy, elderly individuals. MAIN OUTCOME MEASURES: Age at onset and GRN plasma levels. RESULTS: The risk allele of rs1990622 was associated with a mean decrease of the AAO of 13 years (P = 9.9 × 10(-7)) and with lower plasma GRN levels in both healthy older adults (P = 4 × 10(-4)) and GRN mutation carriers (P = .0027). Analysis of the HapMap database identified a nonsynonymous single-nucleotide polymorphism rs3173615 (T185S) in perfect linkage disequilibrium with rs1990622. CONCLUSIONS: The association of rs1990622 with AAO explains, in part, the wide range in the AAO of disease among GRN mutation carriers. We hypothesize that rs1990622 or another variant in linkage disequilibrium could act in a manner similar to APOE in Alzheimer disease, increasing risk for disease in the general population and modifying AAO in mutation carriers. Our results also suggest that genetic variation in TMEM106B may influence risk for FTLD-TDP by modulating secreted levels of GRN.


Assuntos
Degeneração Lobar Frontotemporal/genética , Heterozigoto , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único , Idade de Início , Idoso , Doença de Alzheimer/genética , Substituição de Aminoácidos , Feminino , Degeneração Lobar Frontotemporal/sangue , Expressão Gênica , Predisposição Genética para Doença , Humanos , Estimativa de Kaplan-Meier , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Progranulinas , Modelos de Riscos Proporcionais , Medição de Risco , Fatores de Risco , Serina , Treonina , Fatores de Tempo
7.
Alzheimer Dis Assoc Disord ; 21(1): 1-7, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17334266

RESUMO

Hereditary dysphasic disinhibition dementia (HDDD) describes a familial disorder characterized by personality changes, and language and memory deficits. The neuropathology includes frontotemporal lobar atrophy, neuronal loss and gliosis and, in most cases, abundant Abeta plaques and neurofibrillary tangles (NFTs). A Pick/Alzheimer's spectrum was proposed for the original family (HDDD1). Here we report the clinicopathologic case of an HDDD1 individual using modern immunohistochemical methods, contemporary neuropathologic diagnostic criteria to distinguish different frontotemporal lobar degenerations (FTLDs), and progranulin (PRGN) mutation analysis. Clinical onset was at age 62 years with personality changes and disinhibition, followed by nonfluent dysphasia, and memory loss that progressed to muteness and total dependence with death at age 84 years. There was severe generalized brain atrophy (weight=570 g). Histopathology showed superficial microvacuolation, marked neuronal loss, gliosis, and ubiquitin-positive, tau-negative cytoplasmic and intranuclear neuronal inclusions in frontal, temporal, and parietal cortices. There were also frequent neuritic plaques and NFTs in parietal and occipital cortices. The case met neuropathologic criteria for both FTLD with ubiquitin-positive, tau-negative inclusions (FTLD-U), and Alzheimer disease (Braak NFT stage V). We discovered a novel pathogenic PGRN mutation c.5913 A>G (IVS6-2 A>G) segregating with FTLD-U in this kindred. In conclusion, HDDD1 is an FTLD-U caused by a PGRN mutation and is neuropathologically heterogeneous with Alzheimer disease as a common comorbidity.


Assuntos
Encéfalo/patologia , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Transtornos Heredodegenerativos do Sistema Nervoso/patologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação/genética , Ubiquitina/genética , Idoso , Afasia/etiologia , Afasia/genética , Afasia/patologia , Demência/etiologia , Demência/genética , Demência/patologia , Feminino , Transtornos Heredodegenerativos do Sistema Nervoso/psicologia , Humanos , Inibição Psicológica , Linhagem , Transtornos da Personalidade/etiologia , Transtornos da Personalidade/genética , Transtornos da Personalidade/patologia , Progranulinas
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