RESUMO
Relationships between genes and amyotrophic lateral sclerosis (ALS) have been widely accepted since the first studies highlighting pathogenic mutations in the SOD1 gene 30years ago. Over the last three decades, scientific literature has clearly highlighted the central role played by genetic factors in the disease, in both clinics and pathophysiology, as well as in therapeutics. This implies that health professionals who care for patients with ALS are increasingly faced with patients and relatives eager to have answers to questions related to the role of genetic factors in the occurrence of the disease and the risk for their relatives to develop ALS. In order to address these public health issues, the French ALS network FILSLAN proposed to the Haute Autorité de santé (HAS) the drafting of a French National Protocol (PNDS) on ALS genetics. This PNDS was developed according to the "method for developing a national diagnosis and care protocol for rare diseases" published by the HAS in 2012 (methodological guide for PNDS available on the HAS website: http://www.has-sante.fr/). This document aims to provide the most recent data on the role of genes in ALS and to detail the implications for diagnosis and care.
Assuntos
Esclerose Lateral Amiotrófica , Humanos , Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/epidemiologia , Esclerose Lateral Amiotrófica/genética , MutaçãoRESUMO
Pathophysiology of amyotrophic lateral sclerosis (ALS) remains partially understood even though it is accepted worldwide that motor neuron death results from a pluri-factorial process with a variable role of genetic factors. Although not distinguishable from a clinical point of view, familial forms of ALS (fALS, 10% of cases) and sporadic forms (sALS, 90% of cases) can be described. Since the identification of superoxide dismutase 1 gene (SOD1) mutations, more than 30 genes have been linked to fALS. Among these genes, five (C9ORF72, SOD1, TARDBP, FUS, TBK1) seem predominant with mutation frequencies of 40%, 20%, 5%, <5%, <5% in fALS and 6%, 3%, and <1% for the last three in sALS, respectively. The situation that classically leads to request genetic screening is the presence of a familial history of motor neuron disorders (MND) or fronto-temporal lobar dementia (FTLD). However, this dichotomy between fALS and sALS based on familial history can lead to mistakes since illegitimacy, ignorance of MND, FTD or psychiatric disorders within the family due to a familial censorship or lack of familial relationship, or a recessive autosomal inheritance could wrongly lead to failing to recognize a familial form. The significant development of genetic research and easier access to genetic tests in fALS increase the number of situations for which gene mutations are identified. The consequence is an increase in genetic requests from relatives of ALS patients who are eager to know their own genetic status and their own individual risk to develop ALS. Pre-symptomatic testing is thus becoming a daily issue in ALS Centers. This led us to propose a framework for such pre-symptomatic genetic testing for people at risk for developing ALS.
Assuntos
Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/genética , Testes Genéticos/normas , Esclerose Lateral Amiotrófica/epidemiologia , Doenças Assintomáticas , Confidencialidade/normas , Análise Mutacional de DNA/métodos , Análise Mutacional de DNA/normas , Revelação/normas , Diagnóstico Precoce , Frequência do Gene , Estudos de Associação Genética , Aconselhamento Genético/métodos , Aconselhamento Genético/normas , Predisposição Genética para Doença , Testes Genéticos/métodos , Humanos , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Diagnóstico Molecular/normas , Sintomas ProdrômicosRESUMO
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia is an autosomal dominant leukoencephalopathy related to CSF1R gene mutations. A growing number of clinicoradiologic phenotypes have been described. In this study, we analyzed brain imaging findings in 16 patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia to refine radiologic diagnostic clues. T2/FLAIR white matter hyperintensities were present in all patients with frontal or frontoparietal predilection, with asymmetric distribution in more than one-third. Brain atrophy and callosal involvement were almost constant, and corticospinal tract involvement was frequent. Moreover, deep white matter hyperintense dots on DWI and deep punctate calcifications on CT were often found. Conversely, deep gray matter nuclei, external capsules, and brain stem were rarely involved. Our series emphasized the great variability of MR imaging findings seen in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. A complete imaging screening including DWI, T2*, and CT is mandatory to accurately assess patients with suspected inherited adult-onset leukoencephalopathy.
Assuntos
Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/patologia , Adulto , Feminino , França , Humanos , Leucoencefalopatias/genética , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Neuroimagem/métodosAssuntos
Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/genética , Proteína Huntingtina/genética , Doença de Huntington/genética , Idoso , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Núcleo Familiar , Expansão das Repetições de TrinucleotídeosRESUMO
Etiologic diagnosis of adulthood leukodystrophy is challenging in neurologic practice. We describe here the clinico-radiological features of a novel autosomal dominant leukodystrophy in a single family. Clinical and MRI features were recorded in a three generation family. Exome sequencing was performed in two affected relatives and one healthy member. Four total relatives (3 women and 1 man, mean age at onset: 45, range 32-59) were followed: 2 for migraine and 2 for cognitive loss. MRI features were homogeneous in the four affected relatives: extensive and symmetrical white matter hyperintensities on T2-weighted images, with a posterior predominance, involvement of the middle cerebellar peduncles, corpus callosum and the posterior limb of the internal capsules. An extensive metabolic screening was negative. In addition, sequencing of pathogenic genes involved in dominant leukodystrophies (NOTCH3, LMNB1, GFAP, CSF1R) was negative. No mutation has been identified yet with exome sequencing. This report is peculiar because of dominant inheritance, adult onset, highly homogeneous white matter hyperintensities on T2-weighted MR images, predominant in the middle cerebellar peduncles and posterior part of internal capsule and absence of mutation of the genes involved in dominant leukodystrophies.
Assuntos
Encéfalo/patologia , Leucoencefalopatias/diagnóstico , Imageamento por Ressonância Magnética , Adulto , Exoma , Saúde da Família , Feminino , Testes Genéticos , Proteína Glial Fibrilar Ácida/genética , Humanos , Lamina Tipo B/genética , Leucoencefalopatias/líquido cefalorraquidiano , Leucoencefalopatias/genética , Masculino , Pessoa de Meia-Idade , Mutação , Receptor Notch3 , Receptores Notch/genéticaRESUMO
The role of cholesterol in female reproductive physiology has been suspected for a long time, while the molecular bases were unknown. Cholesterol is the precursor of ovarian steroid biosynthesis and is also essential for fertility. In the uterus, cholesterol is essential to achieve correct contractions at term, but an excessive uterine cholesterol concentration has been associated with contractility defects. Liver X Receptor (LXR) α and LXR ß are nuclear receptors activated by oxysterols, oxidized derivatives of cholesterol. Since their discovery, the role of LXR in the control of cholesterol homeostasis has been widely described. Beyond their cholesterol-lowering role, more recent data have linked these nuclear receptors to various physiological processes. In particular, they control ovarian endocrine and exocrine functions, as well as uterine contractility. Their contribution to female reproductive cancers will also be discussed. This review will try to enlighten on the LXR as a molecular link between dietary cholesterol and reproductive diseases in women. In the future, a better comprehension of the various physiological processes regulated by the LXR will help to develop new ligands to prevent or to cure these pathologies in women.
Assuntos
Colesterol/metabolismo , Fertilidade/fisiologia , Receptores Nucleares Órfãos/metabolismo , Reprodução/fisiologia , Feminino , Humanos , Receptores X do Fígado , MasculinoRESUMO
OBJECTIVE: To describe the phenotype and phenotype-genotype correlations in patients with amyotrophic lateral sclerosis (ALS) with TARDBP gene mutations. METHODS: French TARDBP+ patients with ALS (n = 28) were compared first to 3 cohorts: 737 sporadic ALS (SALS), 192 nonmutated familial ALS (FALS), and 58 SOD1 + FALS, and then to 117 TARDBP+ cases from the literature. Genotype-phenotype correlations were studied for the most frequent TARDBP mutations. RESULTS: In TARDBP+ patients, onset was earlier (p = 0.0003), upper limb (UL) onset was predominant (p = 0.002), and duration was longer (p = 0.0001) than in patients with SALS. TARDBP+ and SOD1+ groups had the longest duration but diverged for site of onset: 64.3% UL onset for TARDBP+ and 74.1% on lower limbs for SOD1+ (p < 0.0001). The clinical characteristics of our 28 patients were similar to the 117 cases from the literature. In Caucasians, 51.3% of had UL onset, while 58.8% of Asians had bulbar onset (p = 0.02). The type of mutation influenced survival (p < 0.0001), and the G298S1, lying in the TARDBP super rich glycine-residue domain, was associated with the worst survival (27 months). CONCLUSION: Differences in phenotype between the groups as well as the differential influence of TARBDP mutations on survival may help physicians in ALS management and allow refining the strategy of genetic diagnosis.
Assuntos
Esclerose Lateral Amiotrófica/genética , Proteínas de Ligação a DNA/genética , Adulto , Idade de Início , Idoso , Esclerose Lateral Amiotrófica/mortalidade , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Análise de SobrevidaRESUMO
Inherited and acquired changes in pre-mRNA processing have significant roles in human diseases, especially cancer. Characterization of aberrantly spliced mRNAs may thus contribute to understand malignant transformation. We recently reported an anti-oncogenic potential for the SOX9 transcription factor in the colon. For instance, the Sox9 gene knock out in the mouse intestine results in an excess of proliferation with appearance of hyperplasia. SOX9 is expressed in colon cancer cells but its endogenous activity is weak. We looked for SOX9 variants that may impair SOX9 activity in colon cancer cells and we discovered MiniSOX9, a truncated version of SOX9 devoid of transactivation domain as a result of retention of the second intron. A significant overexpression of MiniSOX9 mRNA in human tumor samples compared with their matched normal tissues was observed by real-time reverse transcriptase-PCR. Immunohistochemistry revealed that MiniSOX9 is expressed at high levels in human colon cancer samples whereas it is undetectable in the surrounding healthy tissues. Finally, we discovered that MiniSOX9 behaves as a SOX9 inhibitor, inhibits protein kinase Cα promoter activity and stimulates the canonical Wnt pathway. This potential oncogenic activity of the SOX9 locus gives new insights on its role in colon cancer.
Assuntos
Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Fatores de Transcrição SOX9/genética , Fatores de Transcrição SOX9/metabolismo , Adenocarcinoma/patologia , Processamento Alternativo , Animais , Sequência de Bases , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Genes Dominantes , Humanos , Íntrons , Camundongos , Camundongos Mutantes , Dados de Sequência Molecular , Mutação , Regiões Promotoras Genéticas , Proteína Quinase C-alfa/antagonistas & inibidores , Proteína Quinase C-alfa/metabolismo , Fatores de Transcrição SOX9/antagonistas & inibidores , Proteínas Wnt/metabolismoRESUMO
Cholesterol is a structural component of lipid rafts within the plasma membrane. These domains, used as platforms for various signaling molecules, regulate cellular processes including cell survival. Cholesterol contents are tightly correlated with the structure and function of lipid rafts. Liver X receptors (LXRs) have a central role in the regulation of cholesterol homeostasis within the cell. Therefore, we investigated whether these nuclear receptors could modulate lipid raft signaling and consequently alter prostate cancer (PCa) cell survival. Treatment with the synthetic LXR agonist T0901317 downregulated the AKT survival pathway and thus induced apoptosis of LNCaP PCa cells in both xenografted nude mice and cell culture. The decrease in tumor cholesterol content resulted from the upregulation of ABCG1 and the subsequent increase in reverse cholesterol transport. RNA interference experiments showed that these effects were mediated by LXRs. Atomic force microscopy scanning of the inner plasma membrane sheet showed smaller and thinner lipid rafts after LXR stimulation, associated with the downregulation of AKT phosphorylation in these lipid rafts. Replenishment of cell membranes with exogenous cholesterol antagonized these effects, showing that cholesterol is a key modulator in this process. Altogether, pharmacological modulation of LXR activity could thus reduce prostate tumor growth by enhancing apoptosis in a lipid raft-dependent manner.
Assuntos
Apoptose , Microdomínios da Membrana/fisiologia , Receptores Nucleares Órfãos/fisiologia , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/fisiologia , Transdução de Sinais , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/fisiologia , Animais , Carbono-Carbono Ligases/fisiologia , Linhagem Celular Tumoral , Colesterol/metabolismo , Regulação para Baixo , Hidrocarbonetos Fluorados/farmacologia , Receptores X do Fígado , Masculino , Camundongos , Camundongos Nus , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Sulfonamidas/farmacologiaRESUMO
Cytochromes P450 (CYPs) are a superfamily of 57 genes coding for drug metabolizing enzymes and endobiotic metabolizing enzymes (steroids, eicosanoids, vitamins...). This is the main metabolizing enzyme system for foreign compounds, including drugs, which has a primary role in organism protection against potential harmful insults from the environment (pollutants, pesticides...). The CYPs regulation is essentially transcriptional: nuclear receptors are recognized as key mediators for the control of drug metabolizing enzymes. Their ligands are exogenous and also endogenous molecules that can up-regulate or down-regulate these transcription factors. Treatment with drugs or xenobiotics, which are nuclear receptor agonists or antagonists, can lead to severe toxicities, loss of therapeutic effect or endobiotic metabolism disorders. Genetic polymorphisms of these enzymes have an important role in their activity and must be taken into account during drug administration. Then, CYP activity depends on genotype and environment; this is recently used as biomarker to determine human exposure to environmental molecules or to predict the susceptibility to certain pathologies.