RESUMO
Mutated skeletal muscle ryanodine receptor-1 (RYR1) gene is associated with a spectrum of autosomal dominant and recessive RyR1-related disorders with a wide phenotype. This report describes a variable phenotype associated with a previously unreported RYR1 frameshift pathogenic variant, (NM_000540.2) c.12815_12825del; p.Ala4272Glyfs*307, common in Libyan Jews. Clinical and genetic features of 14 carriers from 8 unrelated families were collected. There were 12 heterozygotes and 2 compound heterozygotes. Six heterozygotes (median age 49.8) were asymptomatic, and six (median age 24.5) presented with myopathy (n = 3) or severe arthrogryposis-like features, severe scoliosis, pes planus, post-anesthesia malignant hyperthermia, or cystic hygroma (in a fetus) (n = 1 each). None had an abnormal echocardiogram study or elevated creatine phosphokinase (CPK) levels. One bi-allelic carrier had a severe skeletal phenotype and myopathy; the other was a fetus with a cystic hygroma. Assessment of variant frequency in 447 Libyan Jews who underwent exome testing for unrelated reason yielded a prevalence of 1:55. The RYR1 p.Ala4272Glyfs*307 variant is common in Libyan Jews. It is associated with a broad phenotypic spectrum, with possible presentation among heterozygotes. Further genotype-phenotype studies are essential to delineate the clinical significance of the variant in mono- and bi-allelic carriers.
Assuntos
Heterozigoto , Judeus , Fenótipo , Canal de Liberação de Cálcio do Receptor de Rianodina , Humanos , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Feminino , Masculino , Líbia , Adulto , Pessoa de Meia-Idade , Judeus/genética , Adulto Jovem , Adolescente , Mutação da Fase de Leitura , Criança , Doenças Musculares/genética , IdosoRESUMO
PURPOSE: This study aims to describe the ocular manifestations, treatment, and prognosis of OPMD patients registered in the national Israel OPMD(IsrOPMD) registry. METHODS: Data was prospectively collected from patients referred to the IsrOPMD registry from January 2022 to March 2023. This included patient demographics, medical and ocular history, eye exams, eyelid evaluations, visual field exams, and orthoptic evaluations. RESULTS: 30 patients (15 males, mean age 53 years) were treated in the ocular OPMD clinic, predominantly of Bukhari descent (86.6%). The mean visual acuity was 0.06 logMAR. Twenty-one patients (70%) had eye movement problem, mostly in horizontal gaze. 6(20%) patients' complaint about diplopia. Ptosis surgery was performed in 21(70%) patients, with 17(56.7%) patients underwent frontalis sling surgery and 4(13.3%) patients undergoing levator advancement. The mean Margin reflex distance (MRD1) improved post-surgery (2.28 mm vs. 1.58 mm), but 11(36.6%) patients required more than one ptosis surgery. CONCLUSIONS: The study contributes valuable insights into the ocular aspects of OPMD. It reveals that OPMD patients often experience a range of ocular symptoms, such as ptosis, abnormalities in eye movements, strabismus, and potentially diplopia, which can significantly impact their quality of life. The findings underscore the importance of regular ophthalmological follow-up for these patients to address these symptoms effectively. The study is significant in contributing to the limited but growing knowledge about the ocular manifestations of OPMD and the management of these symptoms to improve the quality of life for patients suffering from this condition.
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BACKGROUND: Deep brain stimulation (DBS) is a well-established treatment option for individuals with advanced Parkinson's disease (PD). The potential influence of the LRRK2 p.G2019S or GBA1 variants on its lasting efficacy and adverse effects should be better characterized. METHODS: We conducted a retrospective single-center case-control study involving PD patients who were carriers of a GBA1 variant (GBA1-PD), the LRRK2 p.G2019S variant (LRRK2-PD), and non-carriers (Nc-PD). All participants underwent DBS and were followed up for at least a year. Assessments before surgery and at 1, 2, 3, 5, and 10 years post-DBS included the following: the Movement Disorder Society's Unified PD Rating Scale (MDS-UPDRS) Part III, Hoehn and Yahr scale, Levodopa Equivalent Daily Dose (LEDD) and non-motor symptoms (psychotic episodes, depressive symptoms, and cognitive decline). RESULTS: The sample was composed of 103 patients (72 males, mean age at DBS surgery 61.5 ± 8.7 years, mean postoperative follow-up 7.0 ± 4.1 years). Of these, 19 were LRRK2-PD, 20 GBA1-PD, and 64 were Nc-PD. No significant differences in motor outcomes were observed between the groups. Compared to the Nc-PD patients, the GBA1-PD patients were at increased risk of both psychotic episodes [hazard ratio (HR) 2.76 (95 % CI: 1.12-6.80), p = 0.027], and cognitive decline [HR 2.28 (95 % CI: 1.04-5.00), p = 0.04]. CONCLUSION: LRRK2 and GBA1 variant status did not affect the motor outcomes of DBS in PD patients. However, GBA1-PD patients were at increased risk for psychosis and cognitive decline. Further studies are required to determine the role of genetic stratification in referral to DBS.
Assuntos
Estimulação Encefálica Profunda , Glucosilceramidase , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Doença de Parkinson , Humanos , Doença de Parkinson/terapia , Doença de Parkinson/genética , Estimulação Encefálica Profunda/efeitos adversos , Masculino , Feminino , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Glucosilceramidase/genética , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Estudos de Casos e Controles , Resultado do Tratamento , SeguimentosRESUMO
OBJECTIVE: Amyloidosis due to the transthyretin Ser77Tyr mutation (ATTRS77Y) is a rare autosomal-dominant disorder, characterized by carpal-tunnel syndrome, poly- and autonomic-neuropathy, and cardiomyopathy. However, related symptoms and signs are often nonspecific and confirmatory tests are required. We describe the age and frequency of early symptoms and diagnostic features among individuals of Jewish Yemenite descent in Israel. METHODS: Records of mutation carriers were retrospectively reviewed. ATTRS77Y diagnosis was defined by the presence of amyloid in tissue and/or amyloid-related cardiomyopathy. RESULTS: We identified the Ser77Tyr mutation at the heterozygous state in 19 amyloidosis patients (mean age at diagnosis: 62 ± 5.7 years, range 49-70) and 30 amyloid-negative carriers. The probability for disease diagnosis increased from 4.4% at age 49 to 100% at 70 and occurred earlier in males. Initial symptoms preceded diagnosis by 5 ± 3.8 years (range 0-12) and were commonly sensory changes in the extremities. Erectile dysfunction predated these in 8/13 (62%) males. In two patients cardiac preceded neurological symptoms. Two patients declined symptoms. Electrophysiological studies near the time of diagnosis indicated a median neuropathy at the wrist in 18/19 (95%) and polyneuropathy in 13/19 (68%). Skin biopsy revealed epidermal denervation in 15/16 (94%) patients. Cardiomyopathy was identified in 16/19 (84%). Sensory complaints or epidermal denervations were present in 17/30 (57%) of amyloid-negative carriers and co-occurred in 10/30 (33%). INTERPRETATION: ATTRS77Y symptoms commonly occur after age 50, but may begin earlier. Median neuropathy, skin denervation and cardiomyopathy are frequently identified. Symptoms may be absent in patients and common in amyloid-negative carriers.
Assuntos
Neuropatias Amiloides Familiares , Cardiomiopatias , Síndrome do Túnel Carpal , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Amiloide , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/patologia , Israel , Estudos Retrospectivos , Pré-Albumina/metabolismoRESUMO
BACKGROUND: Both genetic and environmental factors contribute to Parkinson's disease (PD) risk. OBJECTIVE: We investigated the potential association of several relevant variables with PD age at onset (AAO), focusing on LRRK2 p.G2019S and GBA p.N370S mutations. METHODS: Ashkenazi Jewish (AJ) PD patients, screened for LRRK2 and GBA mutations, underwent an interview regarding exposure to the following environmental and lifestyle factors: cigarette smoking, consumption of coffee, tea and alcohol, head injury and rural living. Multivariate linear regression (adjusted for sex) was used to examine the association with AAO, and models included LRRK2 p.G2019S and GBA p.N370S mutation status (carrier/non-carriers), single environmental variable and their interactions terms, as independent variables. RESULTS: 225 Israeli AJ PD patients were enrolled: 65 LRRK2 p.G2019S mutation carriers, 60 GBA p.N370S carriers and 100 non-carries of these mutations. In the dichotomized exposure/non-exposure analyses, positive LRRK2 p.G2019S status was associated with younger AAO in all models, at nominal or near significant levels (pâ=â0.033-0.082). Smoking was associated with older AAO (pâ=â0.032), and the interaction between GBA p.N370S and history of head injury was associated with younger AAO (pâ=â0.049), both at nominal significance. There was no indication of a consistent main effect for GBA p.N370S status or significant LRRK2 p.G2019S-environmental factor interaction. In the dose-dependent analyses, increased coffee and tea consumption levels were associated with older AAO (pâ=â0.001 and pâ=â0.002, respectively). CONCLUSIONS: Our results suggest that genetic and environmental factors may affect AAO in PD patients, but validation in additional samples is required.
Assuntos
Interação Gene-Ambiente , Glucosilceramidase/genética , Judeus , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Doença de Parkinson , Adulto , Idade de Início , Idoso , Café , Comportamento de Ingestão de Líquido/fisiologia , Feminino , Heterozigoto , Humanos , Israel/etnologia , Judeus/genética , Judeus/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/etnologia , Doença de Parkinson/etiologia , Doença de Parkinson/genética , CháRESUMO
BACKGROUND: This study summarizes the results of prenatal diagnosis due to a history of de novo mutation in a previous pregnancy, in a tertiary center in Israel, over a 10-year period. METHODS: We sorted all cases of de novo mutations from a pool of 2,260 pregnancies for which prenatal molecular diagnosis was applied, between the years 2008 and 2017. We identified 122 molecular prenatal diagnosis performed for de novo mutations, in 90 women. RESULTS: While the total number of yearly prenatal diagnoses stayed stable, a linear increase was detected in the number of cases for which the procedure was done due to a previous de novo mutation: from 3 cases in 2008 to 24 cases in 2017. The most common diseases were Rett syndrome (19), neurofibromatosis Type-1 (12) and Tuberous sclerosis (5). Recurrence occurred in 3 of the 90 women (3.3%) and hotspot mutations were identified in two genes accounting for 11 cases. We did not find a difference in paternal age at first occurrence of the de novo mutation between the study group and the control group. CONCLUSION: The large increase in the annual number of prenatal diagnoses performed due to a previous pregnancy with a de novo mutation reflects the growing understanding regarding the role of these mutations in the pathogenesis of genetic diseases.
Assuntos
Doenças Genéticas Inatas/epidemiologia , Testes Genéticos/estatística & dados numéricos , Diagnóstico Pré-Natal/estatística & dados numéricos , Adulto , Feminino , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Humanos , Israel , Mutação , Gravidez , Centros de Atenção Terciária/estatística & dados numéricosRESUMO
Susceptibility to Parkinson's disease (PD) is believed to involve an interaction between genetic and environmental factors. The role of pesticides as a risk factor of PD and neurodegeneration remains controversial. An asymmetric decrease in ligand uptake on 18F-DOPA positron emission tomography (PET), especially in the dorsal putamen, is a sensitive marker of PD. The aim of this study was to examine the pattern of ligand uptake on 18F-DOPA PET in patients with PD exposed or not exposed to pesticides. The main sample included 26 Israeli patients with PD, 13 who were exposed to pesticides and 13 who were not, matched for age and disease duration. All underwent 18F-DOPA PET imaging, and an asymmetry index of ligand uptake between the ipsilateral and contralateral caudate, putamen, and whole striatum was calculated. No significant between-group differences were found in demographic variables, clinical asymmetry index (P = 0.15), or asymmetry index of ligand uptake in the putamen (P = 0.84), caudate (P = 0.78) and striatum (P = 0.45). Comparison of the 18F-DOPA results of the Israeli cohort with those of 17 non-pesticide-exposed patients with PD from Austria yielded no significant differences, further validating our findings. Our observations suggest that although exposure to pesticides might be a risk factor for PD, it does not have an effect on the asymmetry pattern in the nigrostriatal system over non-exposure. We assume that once the disease process is initiated in pesticide-exposed patients, the pathogenic mechanism does not differ from that of idiopathic PD.
Assuntos
Di-Hidroxifenilalanina/análogos & derivados , Exposição Ambiental/efeitos adversos , Neostriado/metabolismo , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Praguicidas/efeitos adversos , Tomografia por Emissão de Pósitrons , Idoso , Áustria , Estudos de Coortes , Di-Hidroxifenilalanina/farmacocinética , Feminino , Humanos , Israel , Masculino , Pessoa de Meia-Idade , Neostriado/diagnóstico por imagem , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson Secundária/diagnóstico por imagem , Doença de Parkinson Secundária/etiologia , Doença de Parkinson Secundária/metabolismoRESUMO
Diaphanospondylodysostosis (DSD) is a rare autosomal recessive skeletal disorder, characterized mainly by ossification defects in vertebrae, thorax malformations, renal cystic dysplasia and usually death in the perinatal period. DSD is caused by mutations in the bone morphogenetic protein-binding endothelial regulator (BMPER) gene. We describe the prenatal findings of a non-consanguineous Jewish couple (shared Balkan origin), with three affected fetuses that presented with malformations in the spine and chest, reduced ossification of the skull and spine, horseshoe kidney and increased nuchal translucency. The unique combination of these ultrasound (US) features raised the possibility of DSD, which was confirmed by whole exome sequencing (WES) performed on a single fetal DNA and familial segregation. In the three fetuses, a novel homozygous mutation in BMPER (c.410Tâ¯>â¯A; p.Val137Asp) was found. This mutation, which segregated in the family, was not found in 65 controls of Jewish Balkan origin, and in several large databases. Taken together, the combination of a detailed prenatal US examination and WES may be highly effective in confirming the diagnosis of a rare genetic disease, in this case DSD.
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Proteínas de Transporte/genética , Anormalidades Craniofaciais/genética , Disostoses/genética , Costelas/anormalidades , Coluna Vertebral/anormalidades , Anormalidades Craniofaciais/diagnóstico por imagem , Disostoses/diagnóstico por imagem , Homozigoto , Mutação de Sentido Incorreto , Costelas/diagnóstico por imagem , Coluna Vertebral/diagnóstico por imagem , Ultrassonografia Pré-NatalRESUMO
We performed whole exome or genome sequencing in eight multiply affected families with ostensibly isolated congenital anosmia. Hypothesis-free analyses based on the assumption of fully penetrant recessive/dominant/X-linked models obtained no strong single candidate variant in any of these families. In total, these eight families showed 548 rare segregating variants that were predicted to be damaging, in 510 genes. Three Kallmann syndrome genes (FGFR1, SEMA3A, and CHD7) were identified. We performed permutation-based analysis to test for overall enrichment of these 510 genes carrying these 548 variants with genes mutated in Kallmann syndrome and with a control set of genes mutated in hypogonadotrophic hypogonadism without anosmia. The variants were found to be enriched for Kallmann syndrome genes (3 observed vs. 0.398 expected, p = 0.007), but not for the second set of genes. Among these three variants, two have been already reported in genes related to syndromic anosmia (FGFR1 (p.(R250W)), CHD7 (p.(L2806V))) and one was novel (SEMA3A (p.(T717I))). To replicate these findings, we performed targeted sequencing of 16 genes involved in Kallmann syndrome and hypogonadotrophic hypogonadism in 29 additional families, mostly singletons. This yielded an additional 6 variants in 5 Kallmann syndrome genes (PROKR2, SEMA3A, CHD7, PROK2, ANOS1), two of them already reported to cause Kallmann syndrome. In all, our study suggests involvement of 6 syndromic Kallmann genes in isolated anosmia. Further, we report a yet unreported appearance of di-genic inheritance in a family with congenital isolated anosmia. These results are consistent with a complex molecular basis of congenital anosmia.
Assuntos
Síndrome de Kallmann/genética , Transtornos do Olfato/congênito , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Proteínas da Matriz Extracelular/genética , Feminino , Hormônios Gastrointestinais/genética , Humanos , Masculino , Proteínas do Tecido Nervoso/genética , Neuropeptídeos/genética , Transtornos do Olfato/genética , Transtornos do Olfato/patologia , Linhagem , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Semaforina-3A/genética , Sequenciamento do ExomaRESUMO
In recent years, several promising susceptibility loci for late-onset Alzheimer's disease (AD) were discovered, by implementing genome-wide association studies (GWAS) approach. Recent GWAS meta-analysis has demonstrated the association of 19 loci (in addition to the APOE locus) with AD in the European ancestry population at genome-wide significance level. Since Type 2 Diabetes (T2D) is a substantial risk factor for cognitive decline and dementia, the 19 single nucleotide polymorphisms (SNPs) that represent the 19 AD loci were studied for association with performance in episodic memory, a primary cognitive domain affected by AD, in a sample of 848 cognitively normal elderly Israeli Jewish T2D patients. We found a suggestive association of SNP rs6733839, located near the bridging integrator 1 (BIN1) gene, with this phenotype. Controlling for demographic (age, sex, education, disease duration and ancestry) covariates, carriers of two copies of the AD risk allele T (TT genotype) performed significantly worse (p=0.00576; p=0.00127 among Ashkenazi origin sub-sample) in episodic memory compared to carriers of the C allele (CT+CC genotypes). When including additional potential covariates (clinical and APOE genotype), results remained significant (p=0.00769; p=0.00148 among Ashkenazi). Interestingly, as validated in multiple large studies, BIN1 is one of the most established AD risk loci, with a high odds ratio. Although preliminary and require further replications, our findings support a contribution of BIN1 to individual differences in episodic memory performance among T2D patients.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Doença de Alzheimer/genética , Cognição/fisiologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/psicologia , Predisposição Genética para Doença , Memória Episódica , Proteínas Nucleares/genética , Proteínas Supressoras de Tumor/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Feminino , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , RiscoRESUMO
Parkinson's disease (PD) is characterized by loss of melanin-positive dopaminergic neurons in the substantia nigra. Malignant melanoma (MM), a melanocyte-derived neoplasm, occurs with higher than expected frequency among PD patients. Red-haired individuals exhibit a threefold risk for developing MM than dark-haired people; PD risk also increases with lighter hair color. One plausible explanation for the associations between MM, hair color, and PD is the melanocortin-1 receptor (MC1R) gene that plays a key role in hair and skin pigmentation as well as in MM predisposition. We hypothesized that specific MC1R variants may predispose to both MM and PD. Genotyping of the MC1R gene was performed for 16 PD patients with MM (PD+ MM+) and for three sets of age, sex, and ethnically matched controls, including 36 patients with PD (PD+ MM-), 37 with MM (PD- MM+) and 37 with neither diagnosis (PD- MM-). No association was found between MC1R variants and the co-occurrence of PD and MM. The risk for MM was higher in carriers of two MC1R variants versus with no MC1R variant (odds ratio (OR)=5.0, 95% confidence interval (CI) 1.7-14.4, p=0.003). The risk for PD in carriers of two MC1R variants was markedly lower (OR=0.213, 95% CI 0.063-0.725) compared with individuals with no MC1R variant (p=0.013). In this study, MC1R variants were not associated with both MM and PD. Further studies in larger cohorts are necessary to confirm these preliminary results.
Assuntos
Melanoma/genética , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único , Receptor Tipo 1 de Melanocortina/genética , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Melanoma/complicações , Pessoa de Meia-Idade , Doença de Parkinson/complicaçõesRESUMO
BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established therapy for advanced Parkinson's disease (PD). The most common genetic mutation associated with PD identified to date is the G2019S mutation of the LRRK2 gene, which is highly prevalent in the Ashkenazi Jewish population. The effect of STN-DBS surgery in patients carrying this mutation has not been systematically studied. We therefore performed a case-control study to evaluate the impact of the G2019S mutation status on the outcomes of bilateral STN-DBS. METHODS: The study sample included 39 Jewish PD patients with bilateral STN-DBS. Thirteen patients (5 females) were G2019S mutation heterozygous. The control group consisted of 26 PD patients with bilateral STN-DBS, negative for the mutation, matched (2:1) for gender, age at PD onset, and disease duration at surgery. Clinical data including the Unified PD Rating Scale scores (UPDRS), levodopa equivalent daily dose (LEDD), and clinical global impression of change (CGIC) concerning both motor and neuropsychiatric outcome- were available at 3 time points (preoperative baseline, 6-12 months and 3 years postoperatively). RESULTS: Implementing a linear mixed model, a significant improvement (p < 0.05) was found for the whole group concerning reduction in motor UPRDS (off state) and LEDD pre- vs. postoperatively, as expected. No difference in clinical outcome was found between carriers and matched non-carriers at baseline or at postoperative follow-up (up to 3 years). CONCLUSIONS: In our study, STN-DBS outcomes were not influenced by the LRRK2 G2019S mutation, and thus knowledge of carrier status may not be relevant to the considerations of patient selection for surgery.
Assuntos
Estimulação Encefálica Profunda/tendências , Judeus/genética , Mutação/genética , Doença de Parkinson/genética , Proteínas Serina-Treonina Quinases/genética , Núcleo Subtalâmico/fisiologia , Idoso , Estudos de Coortes , Feminino , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico , Doença de Parkinson/terapia , Resultado do TratamentoRESUMO
BACKGROUND: Smoking is a well documented environmental factor that reduces susceptibility to Parkinson's disease (PD). Several genetic variants within the nicotinic cholinergic receptor gene cluster, CHRNA5-CHRNA3-CHRNB4 have been reported to be associated with nicotine dependence (ND), and this association has been validated in multiple studies. OBJECTIVES: Due to the inverse correlation between smoking and PD susceptibility, we investigated whether ND-related genetic variants are associated with age at onset (AAO) of PD among smokers. METHODS: We performed a genetic association study in a sample of 677 Italian PD patients, ages 34-76. 438 had never smoked (NS), and 239 were current or past smokers (ever-smokers, ES). Three independent SNPs within the CHRNA5-CHRNA3-CHRNB4 gene cluster (rs588765, rs16969968, rs578776) were analyzed for association with AAO. RESULTS: We demonstrated an interaction between the rs588765 SNP and smoking status (NS vs. ES) that was nominally significant in its effect on PD AAO (p = 0.04). The rs588765 ND risk allele 'C' was associated with delayed AAO among ES (even when smoking intensity variables are accounted for), but had no significant effect among NS. In the ES group, a dominant model of inheritance was observed: carriers of the 'CC' genotype presented delayed AAO compared to carriers of the 'CT' or 'TT' genotypes. CONCLUSION: Our preliminary results suggest that the ND risk variant, rs588765, has a protective effect in PD, and is associated with later AAO, but only when the individual was previously exposed to nicotine. This may be explained by modulating the neuroprotective effect of chronic nicotine exposure against striatal dopaminergic damage. Further validation studies in additional populations are required.
Assuntos
Idade de Início , Estudos de Associação Genética , Proteínas do Tecido Nervoso/genética , Doença de Parkinson/genética , Receptores Nicotínicos/genética , Fumar/efeitos adversos , Tabagismo/genética , Idoso , Feminino , Estudos de Associação Genética/métodos , Predisposição Genética para Doença/epidemiologia , Variação Genética/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/epidemiologia , Polimorfismo de Nucleotídeo Único , RiscoAssuntos
Moléculas de Adesão Celular Neuronais/genética , Proteínas da Matriz Extracelular/genética , Proteínas do Tecido Nervoso/genética , Reflexo de Sobressalto/genética , Serina Endopeptidases/genética , Adulto , Alelos , Etnicidade , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Israel/epidemiologia , Judeus , Masculino , Polimorfismo de Nucleotídeo Único , Proteína Reelina , Reflexo de Sobressalto/fisiologia , Risco , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Caracteres Sexuais , Fatores Sexuais , Fumar , Adulto JovemRESUMO
OBJECTIVES: Catechol-O-methyltransferase (COMT) may be a risk modifying gene for Nicotine dependence (ND) rather than a direct susceptibility gene for this phenotype. Brain nicotinic cholinergic receptors modulate dopaminergic transmission, and several variants within the neighboring CHRNA5-CHRNA3 genes have been associated with ND. Therefore, it is biologically reasonable to study the interactive contribution of COMT and the CHRNA5 and CHRNA3 genes to ND. METHODS: Using a case-control sample of 90 young, Israeli, Jewish female smokers (FTND ≥ 4) and 108 controls (FTND = 0 during heaviest period of smoking), we studied association with ND of 8 COMT tagging SNPs, their interaction with tagging CHRNA5-A3 SNPs and the role of background, personality, and environmental factors. RESULTS: None of the COMT SNPs were associated directly with ND. In pairwise interaction analysis of SNPs from the two loci (COMT SNP-CHRNA5-CHRNA3 SNP), the interaction of intronic COMT SNP, rs9332377, with CHRNA3 3'UTR SNP rs660652 was significantly associated with ND (p = 0.0005), withstanding correction for multiple testing. CONCLUSION: Addition of the genetic interaction variable into a model of non-genetic ND predictors [parental smoking, novelty seeking (NS), and lifetime history of trauma], substantially increases the percentage of ND variance explained by the model, as well as the percentage of cases correctly identified by it.
Assuntos
Catecol O-Metiltransferase/genética , Expressão Gênica , Receptores Nicotínicos/genética , Fumar/genética , Meio Social , Tabagismo/genética , Tabagismo/psicologia , Adulto , Catecol O-Metiltransferase/metabolismo , Catecol O-Metiltransferase/fisiologia , Feminino , Genótipo , Humanos , Proteínas do Tecido Nervoso/genética , Personalidade , Polimorfismo de Nucleotídeo Único , Risco , Fatores de Risco , Fumar/metabolismo , Fumar/fisiopatologia , Tabagismo/metabolismo , População Branca , Mulheres , Adulto JovemRESUMO
BACKGROUND: There has been a lack of published bench and preclinical data supporting the safety and effectiveness of a noninvasive, nonthermal, focused ultrasound technology for body contouring. METHODS: A series of experiments were conducted with a transcutaneous focused ultrasound device (UltraShape Contour I; UltraShape Inc., Yoqneam, Israel): (1) three-dimensional acoustic field distribution was measured by hydrophone in a water bath; (2) the real-time two-dimensional acoustic field was assessed using optical visualization by a Schlieren system; (3) three-dimensional and Schlieren results were compared in tissue-mimicking gel phantoms and in frozen specimens of porcine subcutaneous fat; and (4) a porcine in vivo preclinical model was used to test safety, selectivity, and efficacy by histological staining of excised skin and subcutaneous fat specimens. RESULTS: Real-time imaging of acoustic field distribution obtained by the Schlieren system, as well as real-time ultrasound visualization, produced stable cavitation both in water and in the gel phantoms. The area where the effect was visible corresponded to the focal area of energy delivered by the system transducer, as measured by the hydrophone. Histologically stained specimens of skin and subcutaneous fat that were excised from porcine studies (n = 14) following treatments (n = 31) demonstrated fat cell lysis and no observable cellular destruction of adjacent blood vessels, nerves, and connective tissue. No epidermal or dermal changes were observed clinically or histologically. CONCLUSIONS: The delivery of noninvasive focused ultrasonic energy has been validated and supported by the basic and preclinical data presented. Future studies will investigate various treatment regimens for improved body-contouring results.
Assuntos
Técnicas Cosméticas , Gordura Subcutânea/citologia , Ultrassom , Animais , Desenho de Equipamento , SuínosRESUMO
Acute intermittent porphyria (AIP) is a neuropathic disease caused by a dominant inherited deficiency in porphobilinogen deaminase (PBGD). We investigated the expression and the degradation of the human PBGD-mutations G748A, G748C and 887insA following transfection into human SH-SY5Y neuroblastoma cells. Mutant proteins exhibited reduced protein expression compared to transfected wild-type (wt) PBGD as revealed by Western blotting. The transcription levels assessed by real-time PCR of these mutant species were identical to those of the wild type. Immuno-fluorescence microscopy revealed reduced cellular distribution of the mutated PBGDs in the cytosol and the nucleus in comparison to the wild-type PBGD. Enhanced cellular accumulation of the mutated and wild-type PBGDs was detected following inhibition of the proteasome by the inhibitors CLBL and hemin. Elevated expression of wt and mutated PBGD protein levels was either achieved by hemin or heme-arginate treatment. On the other hand, enhanced PBGD degradation was achieved by lead poisoning of ALAD in the SH-SY5Y cells concomitant with acceleration of proteasomal activity, most probably by ALAD participation in proteasomal regulation [G.G. Guo, M. Gu, J.D. Etlinger, 240-kDa proteasome inhibitor (CF-2) is identical to delta-aminolevulinic acid dehydratase. J Biol Chem 1994; 269:12399-402.] Our results suggest that the difference in expression between the wild-type and mutant proteins appears to be regulated on the level of protein degradation. In conclusion, we demonstrate that the PBGD cellular pool is controlled by the proteasome activity, which in turn is down regulated by hemin or up-regulated by Pb-ALAD.
Assuntos
Hidroximetilbilano Sintase/genética , Hidroximetilbilano Sintase/metabolismo , Neuroblastoma/enzimologia , Porfiria Aguda Intermitente/genética , Complexo de Endopeptidases do Proteassoma/genética , RNA Mensageiro/metabolismo , Ácido Aminolevulínico , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Inibidores de Cisteína Proteinase/farmacologia , Citoplasma/metabolismo , Regulação da Expressão Gênica , Hemina/farmacologia , Humanos , Lactonas/farmacologia , Intoxicação por Chumbo , Proteínas Mutantes , TransfecçãoRESUMO
Porphobilinogen deaminase (PBGD) is a rate-limiting enzyme of the heme biosynthesis pathway, whose level is elevated in various human tumors. PBGD was observed in both nuclear and cytoplasmic fractions of C6 glioma cells by immunostaining. During mitosis, chromatids were intensely stained for PBGD in comparison to the interphase chromatin. Using the yeast two-hybrid system, we identified RanBPM, the nuclear Ran-binding protein, as an interacting partner of PBGD. During butyrate-induced differentiation of C6, both nuclear and cytoplasmic PBGD levels declined as did Ran protein and its nucleotide exchange factor RCC1. N,N'-hexamethylene bis-acetamide-dependent differentiation resulted in an increase of the cytoplasmic PBGD, whereas nuclear PBGD, Ran protein and RCC1 remained unchanged. mRNA levels of PBGD remained unchanged during stimulation with both butyrate and N,N'-hexamethylene bis-acetamide. The enzymatic activity of PBGD and protoporphyrin IX synthesis in C6 cells were dependent on the differentiation induction agent. We conclude that PBGD possibly has a nuclear role in addition to its cytosolic enzymatic activity required for heme synthesis, which is related to cell transformation and differentiation.
Assuntos
Diferenciação Celular/fisiologia , Núcleo Celular/metabolismo , Glioma/metabolismo , Hidroximetilbilano Sintase/metabolismo , Proteína ran de Ligação ao GTP/metabolismo , Transporte Ativo do Núcleo Celular/fisiologia , Sequência de Aminoácidos , Animais , Células HeLa , Humanos , Dados de Sequência Molecular , Porfirinas/metabolismo , RatosRESUMO
Folding and chromophore cyclization-oxidation processes of green and cyan fluorescent fusion proteins (GFP and CFP) in subcellular microenvironments of transfected C6 glioma cells were studied by multipixel spectrally resolved microscopy (SRM). Discrete time-dependent spectral transitions were characterized during protein folding and chromophore maturation in the cytosol, nucleus, mitochondria, endoplasmic reticulum (ER), and Golgi. Spectral similarity mapping of fluorophore transition phases demarcated spatio-temporal fluorescence correlation at a subcellular level. Folding stages were characterized by a transition from red-shifted spectral populations in the time interval of 7-10 hr after transfection to a fully matured fluorophore emitting typical GFP or CFP fluorescence after 10-15 hr. The nascent protein revealed an initial focal accumulation in cytosol emitting in the range of 580-680 nm. After 10 hr, mixed pixel population spectra were measured and at 15 hr GFP was visualized in the cytoplasm by its specific spectral fingerprints with maxima at 545 nm. For nucleus- and mitochondrion-targeted CFPs, the mature conformer was discovered only in its final destination, whereas intermediate steps of fluorophore synthesis (at 10 hr) were found in the cytoplasm. Enhanced fluorescence maturation was manifested only by the ER-Golgi-targeted CFP after 10 hr post transfection by spectral imaging. Moreover, only remnants of initial intermediate fluorescent pixels were localized externally to the Golgi framework at 15 hr. SRM assessed the competence of ER-Golgi to maintain efficient CFP folding in comparison to the rest of the cellular compartments.