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1.
Can J Neurol Sci ; 41(6): 759-62, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25377888

RESUMO

BACKGROUND: A large hexanucleotide repeat expansion in C9orf72 has been identified as the most common genetic cause in familial amyotrophic lateral sclerosis and frontotemporal dementia. Rapid Eye Movement Sleep Behavior Disorder (RBD) is a sleep disorder that has been strongly linked to synuclein-mediated neurodegeneration. The aim of this study was to evaluate the role of the C9orf72 expansions in the pathogenesis of RBD. METHODS: We amplified the C9orf72 repeat expansion in 344 patients with RBD by a repeat-primed polymerase chain reaction assay. RESULTS: We identified two RBD patients carrying the C9orf72 repeat expansion. Most interestingly, these patients have the same C9orf72 associated-risk haplotype identified in 9p21-linked amyotrophic lateral sclerosis and frontotemporal dementia families. CONCLUSIONS: Our study enlarges the phenotypic spectrum associated with the C9orf72 hexanucleotide repeat expansions and suggests that, although rare, this expansion may play a role in the pathogenesis of RBD.


Assuntos
Expansão das Repetições de DNA/genética , Proteínas/genética , Transtorno do Comportamento do Sono REM/diagnóstico , Transtorno do Comportamento do Sono REM/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína C9orf72 , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
2.
Bioorg Med Chem Lett ; 18(16): 4731-5, 2008 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-18640834

RESUMO

A new method for solid phase parallel synthesis of chemically and conformationally diverse macrocyclic peptidomimetics is reported. A key feature of the method is access to broad chemical and conformational diversity. Synthesis and mechanistic studies on the macrocyclization step are reported.


Assuntos
Química Farmacêutica/métodos , Peptídeos Cíclicos/química , Técnicas de Química Combinatória , Dimerização , Dipeptídeos , Modelos Químicos , Modelos Moleculares , Conformação Molecular , Mimetismo Molecular , Estrutura Molecular , Peptídeos/química , Prata/química , Estereoisomerismo , Relação Estrutura-Atividade
3.
PLoS One ; 10(5): e0128255, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26010953

RESUMO

BACKGROUND: Nunavik Inuit (northern Quebec, Canada) reside along the arctic coastline where for generations their daily energy intake has mainly been derived from animal fat. Given this particular diet it has been hypothesized that natural selection would lead to population specific allele frequency differences and unique variants in genes related to fatty acid metabolism. A group of genes, namely CPT1A, CPT1B, CPT1C, CPT2, CRAT and CROT, encode for three carnitine acyltransferases that are important for the oxidation of fatty acids, a critical step in their metabolism. METHODS: Exome sequencing and SNP array genotyping were used to examine the genetic variations in the six genes encoding for the carnitine acyltransferases in 113 Nunavik Inuit individuals. RESULTS: Altogether ten missense variants were found in genes CPT1A, CPT1B, CPT1C, CPT2 and CRAT, including three novel variants and one Inuit specific variant CPT1A p.P479L (rs80356779). The latter has the highest frequency (0.955) compared to other Inuit populations. We found that by comparison to Asians or Europeans, the Nunavik Inuit have an increased mutation burden in CPT1A, CPT2 and CRAT; there is also a high level of population differentiation based on carnitine acyltransferase gene variations between Nunavik Inuit and Asians. CONCLUSION: The increased number and frequency of deleterious variants in these fatty acid metabolism genes in Nunavik Inuit may be the result of genetic adaptation to their diet and/or the extremely cold climate. In addition, the identification of these variants may help to understand some of the specific health risks of Nunavik Inuit.


Assuntos
Carnitina Aciltransferases/genética , Exoma , Ácidos Graxos/genética , Inuíte/genética , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Carnitina Aciltransferases/metabolismo , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/efeitos adversos , Ácidos Graxos/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxirredução , Quebeque
4.
JAMA Neurol ; 71(4): 470-5, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24566826

RESUMO

IMPORTANCE: The autosomal dominant spinocerebellar ataxias (SCAs) are a complex group of neurodegenerative disorders with significant genetic heterogeneity. Despite the identification of 20 SCA genes, the cause of the disorder in a significant proportion of families with SCA remains unexplained. In 1972, a French-Canadian family segregating a combination of SCA and erythrokeratodermia variabilis (EKV) in an autosomal dominant fashion was described. OBJECTIVE: To map and identify the causative gene in this large family with SCA and EKV using a combination of linkage analysis and whole-exome sequencing. DESIGN, SETTING, AND PARTICIPANTS: A total of 32 individuals from the family have undergone complete neurologic and dermatologic examinations. MAIN OUTCOMES AND MEASURES: Mutations in ELOVL4 have been reported in families with macular degeneration. Recently, homozygous mutations were found in patients with ichthyosis, spastic paraplegia, and severe neurodevelopmental defects. In the present study, we report on a heterozygote mutation in ELOVL4 in affected individuals from the family with SCA and EKV. The mutation segregates with a milder phenotype consisting of early-onset patches of erythema and hyperkeratosis, as well as SCA manifesting in the fourth or fifth decade of life. RESULTS: We describe the mapping and the identification of a c.504G>C transversion in ELOVL4 resulting in the p.L168F substitution. We also provide clinical characterization of the phenotypes in 19 mutation carriers. CONCLUSIONS AND RELEVANCE: We report, to our knowledge, the first mutation in ELOVL4 that is associated with SCA and EKV. This gene encodes a member of the elongase family, which is responsible for the elongation of very long-chain fatty acids (at least 26 carbons). These fatty acids participate in a wide variety of physiological functions, including skin barrier formation and peroxisome ß-oxidation. Overall, these results provide additional insight into the pathogenesis of these complex neurodegenerative disorders.


Assuntos
Eritroceratodermia Variável/genética , Proteínas do Olho/genética , Proteínas de Membrana/genética , Mutação de Sentido Incorreto/genética , Fenótipo , Ataxias Espinocerebelares/genética , Sequência de Aminoácidos , Estudos de Coortes , Eritroceratodermia Variável/diagnóstico , Eritroceratodermia Variável/etnologia , Feminino , Triagem de Portadores Genéticos , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Quebeque/etnologia , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/etnologia
5.
Neurobiol Aging ; 34(6): 1710.e7-9, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23273600

RESUMO

Large repeat expansions in the C9orf72 gene were recently reported to be a major cause of familial amyotrophic lateral sclerosis and frontotemporal dementia. Given some of the clinical and pathologic overlap between these 2 diseases and Parkinson's disease, we sought to evaluate the presence of these expansions in a cohort of French-Canadian patients with Parkinson's disease. No pathologic expansion was found in our cohort of patients suggesting that C9orf72 repeat expansions do not play a major role in the pathogenesis of Parkinson's disease.


Assuntos
Expansão das Repetições de DNA/genética , Doença de Parkinson/diagnóstico , Doença de Parkinson/genética , Proteínas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína C9orf72 , Canadá/epidemiologia , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/epidemiologia , Adulto Jovem
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