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1.
Acta Neuropathol ; 140(3): 341-358, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32601912

RESUMO

Polygenic inheritance plays a central role in Parkinson disease (PD). A priority in elucidating PD etiology lies in defining the biological basis of genetic risk. Unraveling how risk leads to disruption will yield disease-modifying therapeutic targets that may be effective. Here, we utilized a high-throughput and hypothesis-free approach to determine biological processes underlying PD using the largest currently available cohorts of genetic and gene expression data from International Parkinson's Disease Genetics Consortium (IPDGC) and the Accelerating Medicines Partnership-Parkinson's disease initiative (AMP-PD), among other sources. We applied large-scale gene-set specific polygenic risk score (PRS) analyses to assess the role of common variation on PD risk focusing on publicly annotated gene sets representative of curated pathways. We nominated specific molecular sub-processes underlying protein misfolding and aggregation, post-translational protein modification, immune response, membrane and intracellular trafficking, lipid and vitamin metabolism, synaptic transmission, endosomal-lysosomal dysfunction, chromatin remodeling and apoptosis mediated by caspases among the main contributors to PD etiology. We assessed the impact of rare variation on PD risk in an independent cohort of whole-genome sequencing data and found evidence for a burden of rare damaging alleles in a range of processes, including neuronal transmission-related pathways and immune response. We explored enrichment linked to expression cell specificity patterns using single-cell gene expression data and demonstrated a significant risk pattern for dopaminergic neurons, serotonergic neurons, hypothalamic GABAergic neurons, and neural progenitors. Subsequently, we created a novel way of building de novo pathways by constructing a network expression community map using transcriptomic data derived from the blood of PD patients, which revealed functional enrichment in inflammatory signaling pathways, cell death machinery related processes, and dysregulation of mitochondrial homeostasis. Our analyses highlight several specific promising pathways and genes for functional prioritization and provide a cellular context in which such work should be done.


Assuntos
Predisposição Genética para Doença/genética , Lisossomos/metabolismo , Mitocôndrias/metabolismo , Doença de Parkinson/metabolismo , Redes Comunitárias , Neurônios Dopaminérgicos/metabolismo , Perfilação da Expressão Gênica/métodos , Humanos , Herança Multifatorial/fisiologia
2.
BMC Cancer ; 19(1): 660, 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31272399

RESUMO

BACKGROUND: Breast cancer is the most common cancer diagnosed in women worldwide. In developed countries, 80-90% of women will survive five years after diagnosis but the transition from hospital-based care to health self-management and self-efficacy can be difficult. Text messaging programs offer a simple and proven way to provide support to people with chronic diseases. This study aims to test the effectiveness of a text message support program at improving women's health self-efficacy, and physical and mental health outcomes after breast cancer treatments compared to usual care at 6-months and to understand the barriers and enablers to widespread implementation. METHODS: Single-blind randomised control trial (RCT; N = 160) comparing a text message support intervention to usual care in women with breast cancer (recruited from a large tertiary referral hospital in Sydney, Australia). The intervention group will receive a six-month text message support program, which consists of semi-personalised, supportive, lifestyle-focused text messages (4 messages/week) in addition to usual care. The control group will receive usual care without the text message program. Outcomes will be assessed at 6-months. The primary outcome is change in self-efficacy for managing chronic disease. Secondary outcomes include change in clinical outcomes (body mass index), lifestyle outcomes (physical activity levels, dietary behaviours), mood (depression and anxiety scales), quality of life, satisfaction with, and usefulness of the intervention. Analyses will be performed on the principle of intention-to-treat to examine differences between intervention and control groups. DISCUSSION: This study will test if a scalable and cost-effective text-messaging intervention is effective at improving women's health self-efficacy, as well as physical and mental health outcomes. Moreover, this study will provide essential preliminary data to bolster a large multicentre RCT to helpsupport breast cancer survivors throughout recovery and beyond. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry (ANZCTR) number ACTRN12618002020268 , 17 December 2018.


Assuntos
Neoplasias da Mama/terapia , Sobreviventes de Câncer/psicologia , Saúde Mental , Sistemas de Apoio Psicossocial , Envio de Mensagens de Texto , Afeto , Assistência ao Convalescente/métodos , Austrália , Índice de Massa Corporal , Doença Crônica/psicologia , Feminino , Seguimentos , Humanos , Estilo de Vida , Qualidade de Vida , Autocuidado , Autorrelato , Método Simples-Cego , Saúde da Mulher
3.
Cell Tissue Res ; 373(1): 9-20, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29536161

RESUMO

Over the last two decades, we have witnessed a revolution in the field of Parkinson's disease (PD) genetics. Great advances have been made in identifying many loci that confer a risk for PD, which has subsequently led to an improved understanding of the molecular pathways involved in disease pathogenesis. Despite this success, it is predicted that only a relatively small proportion of the phenotypic variability has been explained by genetics. Therefore, it is clear that common heritable components of disease are still to be identified. Dissecting the genetic architecture of PD constitutes a critical effort in identifying therapeutic targets and although such substantial progress has helped us to better understand disease mechanism, the route to PD disease-modifying drugs is a lengthy one. In this review, we give an overview of the known genetic risk factors in PD, focusing not on individual variants but the larger networks that have been implicated following comprehensive pathway analysis. We outline the challenges faced in the translation of risk loci to pathobiological relevance and illustrate the need for integrating big-data by noting success in recent work which adopts a broad-scale screening approach. Lastly, with PD genetics now progressing from identifying risk to predicting disease, we review how these models will likely have a significant impact in the future.


Assuntos
Predisposição Genética para Doença , Doença de Parkinson/genética , Redes Reguladoras de Genes , Estudos de Associação Genética , Heterogeneidade Genética , Humanos , Fatores de Risco
4.
Neuropathol Appl Neurobiol ; 44(5): 506-521, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29181857

RESUMO

AIM: Late-onset Alzheimer's disease (LOAD) accounts for 95% of all Alzheimer's cases and is genetically complex in nature. Overlapping clinical and neuropathological features between AD, FTD and Parkinson's disease highlight the potential role of genetic pleiotropy across diseases. Recent genome-wide association studies (GWASs) have uncovered 20 new loci for AD risk; however, these exhibit small effect sizes. Using NGS, here we perform association analyses using exome-wide and candidate-gene-driven approaches. METHODS: Whole-exome sequencing was performed on 132 AD cases and 53 control samples. Exome-wide single-variant association and gene burden tests were performed for 76 640 nonsingleton variants. Samples were also screened for known causative mutations in familial genes in AD and other dementias. Single-variant association and burden analysis was also carried out on variants in known AD and other neurological dementia genes. RESULTS: Tentative single-variant and burden associations were seen in several genes with kinase and protease activity. Exome-wide burden analysis also revealed significant burden of variants in PILRA (P = 3.4 × 10-5 ), which has previously been linked to AD via GWAS, hit ZCWPW1. Screening for causative mutations in familial AD and other dementia genes revealed no pathogenic variants. Variants identified in ABCA7, SLC24A4, CD33 and LRRK2 were nominally associated with disease (P < 0.05) but did not withstand correction for multiple testing. APOE (P = 0.02) and CLU (P = 0.04) variants showed significant burden on AD. CONCLUSIONS: In addition, polygenic risk scores (PRS) were able to distinguish between cases and controls with 83.8% accuracy using 3268 variants, sex, age at death and APOE ε4 and ε2 status as predictors.


Assuntos
Doença de Alzheimer/genética , Sequenciamento do Exoma/métodos , Predisposição Genética para Doença/genética , Glicoproteínas de Membrana/genética , Receptores Imunológicos/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Masculino , Herança Multifatorial
5.
Physiol Genomics ; 48(1): 1-11, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26487704

RESUMO

Lower muscle strength in midlife predicts disability and mortality in later life. Blood-borne factors, including growth differentiation factor 11 (GDF11), have been linked to muscle regeneration in animal models. We aimed to identify gene transcripts associated with muscle strength in adults. Meta-analysis of whole blood gene expression (overall 17,534 unique genes measured by microarray) and hand-grip strength in four independent cohorts (n = 7,781, ages: 20-104 yr, weighted mean = 56), adjusted for age, sex, height, weight, and leukocyte subtypes. Separate analyses were performed in subsets (older/younger than 60, men/women). Expression levels of 221 genes were associated with strength after adjustment for cofactors and for multiple statistical testing, including ALAS2 (rate-limiting enzyme in heme synthesis), PRF1 (perforin, a cytotoxic protein associated with inflammation), IGF1R, and IGF2BP2 (both insulin like growth factor related). We identified statistical enrichment for hemoglobin biosynthesis, innate immune activation, and the stress response. Ten genes were associated only in younger individuals, four in men only and one in women only. For example, PIK3R2 (a negative regulator of PI3K/AKT growth pathway) was negatively associated with muscle strength in younger (<60 yr) individuals but not older (≥ 60 yr). We also show that 115 genes (52%) have not previously been linked to muscle in NCBI PubMed abstracts. This first large-scale transcriptome study of muscle strength in human adults confirmed associations with known pathways and provides new evidence for over half of the genes identified. There may be age- and sex-specific gene expression signatures in blood for muscle strength.


Assuntos
Envelhecimento/fisiologia , Coração/fisiologia , Força Muscular/genética , RNA Mensageiro/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Ontologia Genética , Humanos , Joelho/fisiologia , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Caracteres Sexuais , Adulto Jovem
7.
Mol Psychiatry ; 20(1): 133-39, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24863145

RESUMO

Although overweight and obesity are associated with poor health outcomes in the elderly, the biological bases of obesity-related behaviors during aging are poorly understood. Common variants in the FTO gene are associated with adiposity in children and younger adults as well as with adverse mental health in older individuals. However, it is unclear whether FTO influences longitudinal trajectories of adiposity and other intermediate phenotypes relevant to mental health during aging. We examined whether a commonly carried obesity-risk variant in the FTO gene (rs1421085 single-nucleotide polymorphism) influences adiposity and is associated with changes in brain function in participants within the Baltimore Longitudinal Study of Aging, one of the longest-running longitudinal aging studies in the United States. Our results show that obesity-related risk allele carriers of FTO gene show dose-dependent increments in body mass index during aging. Moreover, the obesity-related risk allele is associated with reduced medial prefrontal cortical function during aging. Consistent with reduced brain function in regions intrinsic to impulse control and taste responsiveness, risk allele carriers of FTO exhibit dose-dependent increments in both impulsivity and intake of fatty foods. We propose that a common neural mechanism may underlie obesity-associated impulsivity and increased consumption of high-calorie foods during aging.


Assuntos
Adiposidade/genética , Envelhecimento/genética , Comportamento Alimentar/fisiologia , Comportamento Impulsivo/fisiologia , Polimorfismo de Nucleotídeo Único/genética , Proteínas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Índice de Massa Corporal , Encéfalo/diagnóstico por imagem , Dieta , Ingestão de Alimentos/genética , Feminino , Genótipo , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Obesidade/genética , Cintilografia , Estados Unidos , Adulto Jovem
8.
Mol Psychiatry ; 20(12): 1588-95, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25687773

RESUMO

We investigated the genetic overlap between Alzheimer's disease (AD) and Parkinson's disease (PD). Using summary statistics (P-values) from large recent genome-wide association studies (GWAS) (total n=89 904 individuals), we sought to identify single nucleotide polymorphisms (SNPs) associating with both AD and PD. We found and replicated association of both AD and PD with the A allele of rs393152 within the extended MAPT region on chromosome 17 (meta analysis P-value across five independent AD cohorts=1.65 × 10(-7)). In independent datasets, we found a dose-dependent effect of the A allele of rs393152 on intra-cerebral MAPT transcript levels and volume loss within the entorhinal cortex and hippocampus. Our findings identify the tau-associated MAPT locus as a site of genetic overlap between AD and PD, and extending prior work, we show that the MAPT region increases risk of Alzheimer's neurodegeneration.


Assuntos
Doença de Alzheimer/genética , Doença de Parkinson/genética , Proteínas tau/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Apolipoproteínas E/genética , Encéfalo/patologia , Cromossomos Humanos Par 17 , Feminino , Loci Gênicos , Pleiotropia Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
9.
Eur J Neurol ; 20(3): 486-492, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23043354

RESUMO

BACKGROUND AND PURPOSE: Autosomal recessive cerebellar ataxia (ARCA) comprises a large and heterogeneous group of neurodegenerative disorders. We studied three families diagnosed with ARCA. METHODS: To determine the gene lesions responsible for their disorders, we performed high-density single-nucleotide polymorphism genotyping and exome sequencing. RESULTS: We identified a new mutation in the SACS gene and a known mutation in SPG11. Notably, we also identified a homozygous variant in APOB, a gene previously associated with ataxia. CONCLUSIONS: These findings demonstrate that exome sequencing is an efficient and direct diagnostic tool for identifying the causes of complex and genetically heterogeneous neurodegenerative diseases, early-stage disease or cases with limited clinical data.


Assuntos
Exoma/genética , Proteínas de Choque Térmico/genética , Proteínas/genética , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/genética , Adolescente , Idade de Início , Sequência de Aminoácidos , Apolipoproteínas B/genética , Sequência de Bases , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Linhagem , Polimorfismo de Nucleotídeo Único , Adulto Jovem
10.
N Engl J Med ; 361(17): 1651-61, 2009 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-19846850

RESUMO

BACKGROUND: Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher's disease, among patients with Parkinson's disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson's disease. METHODS: Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson's disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel-Haenszel procedure used to estimate odds ratios across centers. RESULTS: All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations. CONCLUSIONS: Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson's disease.


Assuntos
Glucosilceramidase/genética , Mutação , Doença de Parkinson/genética , Idoso , Estudos de Casos e Controles , Genótipo , Humanos , Judeus/genética , Modelos Logísticos , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances
11.
Clin Genet ; 80(2): 104-9, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21651510

RESUMO

Exome sequencing is rapidly becoming a fundamental tool for genetics and functional genomics laboratories. This methodology has enabled the discovery of novel pathogenic mutations causing mendelian diseases that had, until now, remained elusive. In this review, we discuss not only how we envisage exome sequencing being applied to a complex disease, such as Parkinson's disease, but also what are the known caveats of this approach.


Assuntos
Éxons/genética , Genoma/genética , Doença de Parkinson/genética , Análise de Sequência de DNA , Animais , Humanos , Mutação , Doença de Parkinson/diagnóstico
12.
Eur J Neurol ; 18(3): 382-6, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20649903

RESUMO

BACKGROUND AND PURPOSE: To characterize patients with benign essential blepharospasm (BEB) by diagnosis, environmental risk factors, and family history. METHODS: Two hundred and forty patients with BEB were evaluated through a clinical examination and questionnaire. The questionnaire reviewed personal medical history, demographic factors, risk factors for the development of blepharospasm and family history of dystonia and other neurological conditions. RESULTS: Benign essential blepharospasm was more commonly found in women (2.8:1) and 93% of the patients were Caucasian. Fifty percent had pure BEB, 31% had BEB/Meige's syndrome, and 4% had BEB and eyelid opening apraxia (+/- Meige's syndrome). A minority of patients reported preceding photophobia (25%) or other eye conditions (22%). The majority were non-smokers, had no exposure to anti-emetic or antipsychotic agents, had a normal birth history, and had no history of head trauma. Seventy-two percent did report a stressful event immediately prior to the development of symptoms. Treatments reported included botulinum toxin (BoNT), oral medications, surgical procedures, and acupuncture. Thirty-two percent of patients reported a family history of focal dystonia, and BEB was the most commonly reported. CONCLUSION: This study confirms previous reports of usual age, sex, caffeine and tobacco use, and family history in patients with blepharospasm. New findings include a report on occupation, lower reports of preceding eye conditions and photophobia, and higher reported stressful events. Further, this study shows a change in treatment with an increase in BoNT use and decrease in surgical procedures.


Assuntos
Blefarospasmo , Adulto , Idade de Início , Blefarospasmo/complicações , Distúrbios Distônicos/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fatores de Risco
13.
Neurogenetics ; 11(3): 313-8, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20039086

RESUMO

We identified a family in Mali with two sisters affected by spastic paraplegia. In addition to spasticity and weakness of the lower limbs, the patients had marked atrophy of the distal upper extremities. Homozygosity mapping using single nucleotide polymorphism arrays showed that the sisters shared a region of extended homozygosity at chromosome 19p13.11-q12 that was not shared by controls. These findings indicate a clinically and genetically distinct form of hereditary spastic paraplegia with amyotrophy, designated SPG43.


Assuntos
Neurite do Plexo Braquial/genética , Cromossomos Humanos Par 19/genética , Loci Gênicos , Paraplegia Espástica Hereditária/genética , Adolescente , Idade de Início , Feminino , Homozigoto , Humanos , Mali , Linhagem , Polimorfismo de Nucleotídeo Único , Irmãos , Adulto Jovem
14.
J Intern Med ; 267(2): 139-55, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20175863

RESUMO

In this review, we discuss the genetic factors in both the aetiology and treatment of ischaemic stroke. We discuss candidate gene association studies, family linkage studies and the more recent whole genome association studies and whole genome expression studies. We also briefly discuss genetic testing for stroke risk and genetic analysis of treatment complications.


Assuntos
Isquemia Encefálica/genética , Acidente Vascular Cerebral/genética , Isquemia Encefálica/terapia , Ligação Genética , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Acidente Vascular Cerebral/terapia
15.
J Med Genet ; 46(6): 375-81, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19351622

RESUMO

BACKGROUND: Mutations in parkin and PTEN-induced protein kinase (PINK1) represent the two most common causes of autosomal recessive parkinsonism. The possibility that heterozygous mutations in these genes also predispose to disease or lower the age of disease onset has been suggested, but currently there is insufficient data to verify this hypothesis conclusively. OBJECTIVE: To study the frequency and spectrum of parkin and PINK1 gene mutations and to investigate the role of heterozygous mutations as a risk factor for early-onset Parkinson's disease (PD). METHODS: All exons and exon-intron boundaries of PINK1 and parkin were sequenced in 250 patients with early-onset PD and 276 normal controls. Gene dosage measurements were also performed, using high-density single-nucleotide polymorphism arrays. RESULTS: In total 41 variants were found, of which 8 have not been previously described (parkin: p.A38VfsX6, p.C166Y, p.Q171X, p.D243N, p.M458L; PINK1: p.P52L, p.T420T, p.A427E). 1.60% of patients were homozygous or compound heterozygous for pathogenic mutations. Heterozygosity for pathogenic parkin or PINK1 mutations was over-represented in patients compared with healthy controls (4.00% vs. 1.81%) but the difference was not significant (p = 0.13). The mean age at disease onset was significantly lower in patients with homozygous or compound heterozygous mutations than in patients with heterozygous mutations (mean difference 11 years, 95% CI 1.4 to 20.6, p = 0.03). There was no significant difference in the mean age at disease onset in heterozygous patients compared with patients without a mutation in parkin or PINK1 (mean difference 2 years, 95% CI -3.7 to 7.0, p = 0.54). CONCLUSIONS: Our data support a trend towards a higher frequency of heterozygosity for pathogenic parkin or PINK1 mutations in patients compared with normal controls, but this effect was small and did not reach significance in our cohort of 250 cases and 276 controls.


Assuntos
Predisposição Genética para Doença , Mutação , Doença de Parkinson/genética , Proteínas Quinases/genética , Ubiquitina-Proteína Ligases/genética , Adolescente , Adulto , Sequência de Aminoácidos , Estudos de Casos e Controles , Criança , Estudos de Coortes , Interpretação Estatística de Dados , Feminino , Dosagem de Genes , Frequência do Gene , Triagem de Portadores Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Alinhamento de Sequência , Análise de Sequência de DNA
16.
Neurogenetics ; 10(3): 183-90, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19271249

RESUMO

Large tracts of extended homozygosity are more prevalent in outbred populations than previously thought. With the advent of high-density genotyping platforms, regions of extended homozygosity can be accurately located allowing for the identification of rare recessive risk variants contributing to disease. We compared measures of extended homozygosity (greater than 1 Mb in length) in a population of 837 late-onset Alzheimer's disease (LOAD) cases and 550 controls. In our analyses, we identify one homozygous region on chromosome 8 that is significantly associated with LOAD after adjusting for multiple testing. This region contains seven genes from which the most biologically plausible candidates are STAR, EIF4EBP1, and ADRB3. We also compared the total numbers of homozygous runs and the total length of these runs between cases and controls, showing a suggestive difference in these measures (p-values 0.052-0.062). This research suggests a recessive component to the etiology of LOAD.


Assuntos
Doença de Alzheimer/genética , Predisposição Genética para Doença , Genética Populacional , Genoma Humano , Análise de Sequência de DNA , Idade de Início , Cromossomos Humanos Par 8 , Genótipo , Humanos , Dados de Sequência Molecular
18.
Eur J Neurol ; 15(10): 1065-70, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18717728

RESUMO

BACKGROUND: Autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum is a distinct and usually severe form of complex hereditary spastic paraplegia classified as SPG11. Recently mutations on SPG11 gene (KIAA1840), which is localized to chromosome 15q13-q15, were shown to cause the majority of SPG11 cases. METHODS: We analysed the 40 coding exons of this gene in the probands from eight families with complex ARHSP, four of these families had a thin corpus callosum and two has mild thinning. RESULTS: Three families were identified with novel mutations in the SPG11 gene. One family was of Asian origin with a homozygous nonsense mutation and had a very severe phenotype but only very mild thinning of the corpus callosum. In the other two English families the parents were unrelated and the mutations were compound heterozygotes. In these two families the phenotype was mild and both probands had a thin corpus callosum. CONCLUSION: Given the probable mechanism of action of the mutations in the Spatacsin gene, we discuss the probable genotype phenotype correlations in these families. This study confirms the frequent occurrence of Spatacsin mutations in complex ARHSP with genotype phenotype effects and exposes the spectrum of clinical heterogeneity in SPG11.


Assuntos
Mutação , Proteínas/genética , Paraplegia Espástica Hereditária/genética , Adolescente , Adulto , Códon sem Sentido , Transtornos Cognitivos/genética , Consanguinidade , Corpo Caloso/patologia , Análise Mutacional de DNA , Feminino , Heterogeneidade Genética , Genótipo , Humanos , Íntrons/genética , Masculino , Linhagem , Fenótipo , Proteínas/química , Proteínas/fisiologia , Sítios de Splice de RNA/genética
19.
Eur J Neurol ; 15(7): 692-6, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18435766

RESUMO

BACKGROUND AND PURPOSE: Mutations in LRRK2, encoding leucine-rich repeat kinase 2 (or Dardarin), cause autosomal dominant Parkinson's disease (AdPD) and are also found in sporadic PD (sPD). To investigate the frequency of LRRK2 mutations in a sample of Russian PD patients. METHODS: We sequenced the complete coding region of LRRK2 in 65 patients with AdPD and in 30 patients with sPD. Furthermore, in 20 patients with AdPD and in 159 patients with sPD we screened several common LRRK2 mutations (G2019S, R1441C/G/H, I2012T and I2020T). RESULTS: Five AdPD patients had the LRRK2 G2019S mutation (5.9%, 5/85). In addition, we discovered a novel LRRK2 variant V1613A in a family with a tremor dominant form of AdPD; this variant was not present in controls. We identified two patients with LRRK2 mutations in sPD: one with the G2019S mutation (0.5; 1/189) and another with the previously described R1441C mutation (0,5; 1/189). CONCLUSIONS: LRRK2 mutations are common amongst patients with PD in Russia. The results also show that the G2019S mutation is the most frequent. We identified one novel mutation in a functional region of LRRK2.


Assuntos
Testes Genéticos , Doença de Parkinson/genética , Proteínas Serina-Treonina Quinases/genética , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Reação em Cadeia da Polimerase , Federação Russa
20.
J Neurol Neurosurg Psychiatry ; 78(7): 754-6, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17371905

RESUMO

OBJECTIVE: Mutations in the progranulin (PGRN) gene were recently described as the cause of ubiquitin positive frontotemporal dementia (FTD). Clinical and pathological overlap between amyotrophic lateral sclerosis (ALS) and FTD prompted us to screen PGRN in patients with ALS and ALS-FTD. METHODS: The PGRN gene was sequenced in 272 cases of sporadic ALS, 40 cases of familial ALS and in 49 patients with ALS-FTD. RESULTS: Missense changes were identified in an ALS-FTD patient (p.S120Y) and in a single case of limb onset sporadic ALS (p.T182M), although the pathogenicity of these variants remains unclear. CONCLUSION: PGRN mutations are not a common cause of ALS phenotypes.


Assuntos
Esclerose Lateral Amiotrófica/complicações , Esclerose Lateral Amiotrófica/genética , Demência/etiologia , Demência/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Fenótipo , Progranulinas
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