RESUMO
Mutations in the progranulin (PGRN) gene were recently described as the cause of ubiquitin positive frontotemporal dementia (FTD) in many families. Different frequencies of these genetic changes have been reported in diverse populations leading us to determine if these mutations were a major cause of FTD in the Portuguese population. The entire coding sequence plus exon 0 of PGRN were sequenced in a consecutive series of 46 FTD/CBS Portuguese patients. Two mutations were found: a novel pathogenic insertion (p.Gln300GlnfsX61) and a previously described point variant (p.T182M) of unclear pathogenicity. Pathogenic mutations in the PGRN gene were found in one of the 36 probands studied (3% of the probands in our series) who had a corticobasal syndrome presentation, indicating that in the Portuguese population, mutations in this gene are not a major cause of FTD.
Assuntos
Demência/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação/genética , Análise Mutacional de DNA , Proteínas de Ligação a DNA/metabolismo , Demência/metabolismo , Saúde da Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Portugal/epidemiologia , ProgranulinasRESUMO
OBJECTIVE: To identify new genes and risk factors associated with frontotemporal dementia (FTD). Several genes and loci have been associated with different forms of FTD, but a large number of families with dementia do not harbor mutations in these genes. DESIGN: Whole-exome sequencing and whole-genome genotyping were performed in all patients. Genetic variants obtained from whole-exome sequencing were integrated with the data obtained from whole-genome genotyping. SETTING: Database of the Behavioral Neurology Outpatient Clinic of the Department of Neurology, Istanbul Faculty of Medicine, Istanbul, Turkey. PATIENTS Forty-four Turkish patients with an FTD-like clinical diagnosis were included in the study. Relatives were screened when appropriate. MAIN OUTCOME MEASURE: Mutations in the triggering receptor expressed on myeloid cells 2 gene (TREM2). RESULTS: In 3 probands with FTD-like disease, we identified different homozygous mutations in TREM2 that had previously been associated with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). None of these 3 patients had a typical clinical presentation of PLOSL: they presented with behavioral change and subsequent cognitive impairment and motor features but without any bone cysts or bone-associated phenotypes. Imaging showed white matter abnormalities as well as frontal atrophy in all 3 patients. CONCLUSIONS: Our results show that TREM2 is responsible for an unexpectedly high number of dementia cases in our cohort, suggesting that this gene should be taken into account when mutations in other dementia genes are excluded. Even for complex syndromes such as dementia, exome sequencing has proven to be a rapid and cost-effective tool to identify genetic mutations, allowing for the association of clinical phenotypes with unexpected molecular underpinnings.
Assuntos
Exoma/genética , Demência Frontotemporal/genética , Glicoproteínas de Membrana/genética , Mutação/genética , Receptores Imunológicos/genética , Adulto , Demência Frontotemporal/patologia , Demência Frontotemporal/fisiopatologia , Humanos , Masculino , Fatores de Risco , SíndromeRESUMO
Alzheimer's disease (AD) is a genetically complex disorder for which the definite diagnosis is only accomplished postmortem. Mutations in 3 genes (APP, PSEN1, and PSEN2) are known to cause AD, but a large number of familial cases do not harbor mutations in these genes and several unidentified genes that contain disease-causing mutations are thought to exist. We performed whole exome sequencing in a Turkish patient clinically diagnosed with Alzheimer's disease from a consanguineous family with a complex history of neurological and immunological disorders and identified a mutation in NOTCH3 (p.R1231C), previously described as causing cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Complete screening of NOTCH3 in a cohort of 95 early onset AD cases and 95 controls did not reveal any additional pathogenic mutations. Although the complex history of disease in this family precluded us to establish segregation of the mutation found with disease, our results show that exome sequencing is a rapid, cost-effective and comprehensive tool to detect genetic mutations, allowing for the identification of unexpected genetic causes of clinical phenotypes. As etiological based therapeutics become more common, this method will be key in diagnosing and treating disease.
Assuntos
Doença de Alzheimer/genética , Exoma/genética , Receptores Notch/genética , Análise de Sequência de DNA , Adulto , Idoso , Idoso de 80 Anos ou mais , Saúde da Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Mutação Puntual/genética , Receptor Notch3 , TurquiaRESUMO
Mutations in three genes (PSEN1, PSEN2, and APP) have been identified in patients with early-onset (<65 years) Alzheimer's disease (AD). We performed a screening for mutations in the coding regions of presenilins, as well as exons 16 and 17 of the APP gene in a total of 231 patients from the Iberian peninsular with a clinical diagnosis of early-onset AD (mean age at onset of 52.9 years; range 31-64). We found three novel mutations in PSEN1, one novel mutation in PSEN2, and a novel mutation in the APP gene. Four previously described mutations in PSEN1 were also found. The same analysis was carried in 121 elderly healthy controls from the Iberian peninsular, and a set of 130 individuals from seven African populations belonging to the Centre d'Etude du Polymorphisme Humain-Human Genome Diversity Panel (CEPH-HGDP), in order to determine the extent of normal variability in these genes. Interestingly, in the latter series, we found five new non-synonymous changes in all three genes and a presenilin 2 variant (R62H) that has been previously related to AD. In some of these mutations, the pathologic consequence is uncertain and needs further investigation. To address this question we propose and use a systematic algorithm to classify the putative pathology of AD mutations.
Assuntos
Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Presenilina-1/genética , Presenilina-2/genética , Adulto , África , Idoso , Éxons/genética , Predisposição Genética para Doença/genética , Testes Genéticos , Humanos , Pessoa de Meia-Idade , Mutação/genética , Portugal , EspanhaRESUMO
BACKGROUND: Several lines of evidence in the literature have shown that inflammation is involved in the pathogenesis of Alzheimer's disease (AD). However, the results from the evaluation of serum inflammatory markers in AD patients have been controversial. OBJECTIVE: To determine if any differences exist in the monocytic secretion pattern of IL-1beta, IL-6, IL-12 and TNF-alpha from mild cognitive impairment (MCI) and AD patients, when compared with healthy age-matched controls. METHODS: To evaluate the percentage of peripheral monocytes secreting IL-1beta, IL-6, IL-12 and TNF-alpha along with the relative levels of these proteins, a cytofluorimetric analysis was conducted under basal conditions and after lipopolysaccharide-induced cell activation. RESULTS: We found, in AD and MCI patients, a significant raise in the percentage of monocytes producing the studied cytokines (under basal conditions and after the exposure to an inflammatory stimulus), as well as a decreased competence of these cells to respond to inflammatory challenges, when compared with controls. CONCLUSIONS: These results agree with a persistent inflammatory status in AD, reinforcing the hypothesis of a progressive impairment of the immune response in this disorder and suggesting that monocytes may be good targets to study the progression from MCI to AD.
Assuntos
Doença de Alzheimer/sangue , Transtornos Cognitivos/sangue , Citocinas/metabolismo , Inflamação/metabolismo , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Biomarcadores/sangue , Estudos de Casos e Controles , Citocinas/classificação , Feminino , Citometria de Fluxo/métodos , Humanos , Inflamação/induzido quimicamente , Lipopolissacarídeos/farmacologia , Masculino , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/metabolismoRESUMO
LRRK2 mutations have recently been described in families with Parkinson's disease. Here we show that one of them (G2019S) is present in 6% (7 of 124) unrelated cases of disease in a clinic-based sample series from central Portugal, but not present in 126 controls from the same population. Thus, LRRK2 mutations appear to be a common cause of typical Parkinson's disease and as such will alter clinical practice.