RESUMO
Parkinson's disease (PD) is a common neurodegenerative disorder of complex aetiology. Rare, highly penetrant PD-causing mutations and common risk factors of small effect size have been identified in several genes/loci. However, these mutations and risk factors only explain a fraction of the disease burden, suggesting that additional, substantial genetic determinants remain to be found. Genetically isolated populations offer advantages for dissecting the genetic architecture of complex disorders, such as PD. We performed exome sequencing in 100 unrelated PD patients from Sardinia, a genetic isolate. SNPs absent from dbSNP129 and 1000 Genomes, shared by at least five patients, and of functional effects were genotyped in an independent Sardinian case-control sample (n = 500). Variants associated with PD with nominal p value <0.05 and those with odds ratio (OR) ≥3 were validated by Sanger sequencing and typed in a replication sample of 2965 patients and 2678 controls from Italy, Spain, and Portugal. We identified novel moderately rare variants in several genes, including SCAPER, HYDIN, UBE2H, EZR, MMRN2 and OGFOD1 that were specifically present in PD patients or enriched among them, nominating these as novel candidate risk genes for PD, although no variants achieved genome-wide significance after Bonferroni correction. Our results suggest that the genetic bases of PD are highly heterogeneous, with implications for the design of future large-scale exome or whole-genome analyses of this disease.
Assuntos
Exoma , Mutação , Doença de Parkinson/genética , Estudos de Casos e Controles , Análise Mutacional de DNA , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Itália/epidemiologia , Masculino , Doença de Parkinson/epidemiologia , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
Genetic factors play a major role in the etiology of juvenile myoclonic epilepsy (JME), a common form of idiopathic generalized epilepsy, but so far, genes related to JME remain largely unknown. JME shares electroclinical features with Unverricht-Lundborg disease (progressive myoclonic epilepsy type 1; EPM1), a form of progressive myoclonus epilepsy characterized by myoclonus, epilepsy, and gradual neurologic deterioration. EPM1 is caused by mutations in the gene that codes for cystatin B (CSTB), an inhibitor of cysteine protease. In the present study, we wished to investigate the role of the CSTB gene in patients with JME. Fifty-seven unrelated patients (35 women; mean age ± standard deviation [SD], 24.1 ± 7.7; mean age ± SD at onset, 15.3 ± 2.4) with JME were enrolled. Twenty-three of 57 patients were the probands of families with JME. The molecular diagnosis was carried out to identify the common dodecamer repeat expansion mutation or other disease-causing mutations in the CSTB gene. The molecular analysis did not depict mutations in any of the 57 patients with JME. Our study did not support a role for the CSTB gene in patients with familial or sporadic JME.
Assuntos
Cistatina B/genética , Epilepsia Mioclônica Juvenil/diagnóstico , Epilepsia Mioclônica Juvenil/genética , Adolescente , Adulto , Feminino , Humanos , Masculino , Mutação/genética , Adulto JovemRESUMO
BACKGROUND: Idiopathic basal ganglia calcification (IBGC), also known as Fahr's disease, is a rare disorder characterized by widespread cerebral calcifications, an autosomal dominant pattern of inheritance and clinical and genetic heterogeneity. The recently identified IBGC gene, SLC20A2, encodes for type III sodium-dependent phosphate transporter 2 and its loss-of-function mutations may lead to the regional accumulation of inorganic phosphate in the brain, causing calcium phosphate deposition. OBJECTIVE: To describe the clinical, neuroimaging and genetic findings in an Italian family with IBGC. METHODS: The family members underwent clinical and radiological examination in order to diagnose IBGC according to standard criteria and screening for SLC20A2 gene mutations. The affected subjects also underwent neuropsychological longitudinal assessments and functional neuroimaging investigations. RESULTS: The 2 affected family members harbored a novel missense mutation, G1618A, in the SLC20A2 gene, leading to gly540-to-arg (G540R) substitution in a highly conserved residue. This is the first SLC20A2 gene mutation associated with familial IBGC reported in the Italian population and is damaging according to all prediction programs. In the index case we observed a fair correlation between cortical areas with no calcifications but with significant hypometabolism at [18F]FDG-PET (inferior frontal premotor cortex) and the neuropsychological picture dominated by dynamic aphasia and buccofacial apraxia. CONCLUSION: These findings expand the catalog of SLC20A2 mutations identified to date and add dynamic aphasia to the spectrum of neuropsychological deficits reported in IBGC, supporting the use of functional neuroimaging studies for better investigation of genotype-phenotype correlations.
Assuntos
Afasia/genética , Afasia/fisiopatologia , Doenças dos Gânglios da Base/genética , Doenças dos Gânglios da Base/fisiopatologia , Calcinose/genética , Calcinose/fisiopatologia , Mutação de Sentido Incorreto , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/fisiopatologia , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/genética , Idoso , Afasia/patologia , Doenças dos Gânglios da Base/patologia , Encéfalo/patologia , Calcinose/patologia , Família , Feminino , Seguimentos , Humanos , Itália , Estudos Longitudinais , Masculino , Doenças Neurodegenerativas/patologia , Linhagem , Adulto JovemRESUMO
PURPOSE: To report the identification of the T1174S SCN1A (NaV 1.1) mutation in a three-generation family with both epileptic and familial hemiplegic migraine (FHM) phenotypes and clarify the pathomechanism. METHODS: The five affected individuals underwent detailed clinical analyses. Mutation analyses was performed by direct sequencing of SCN1A; functional studies by expression in tsA-201 cells. A computational model was used to compare the effects of T1174S with those of a typical FHM mutation (Q1489K). KEY FINDINGS: The proband had benign occipital epilepsy (BOE); two relatives had simple febrile seizures (FS) and later developed BOE. Two additional relatives had FHM without epilepsy or FS. All affected members and one obliged carrier carried the T1174S mutation. Functional effects were divergent: positive shift of the activation curve and deceleration of recovery from fast inactivation, consistent with loss of function, and increase of persistent current (I(NaP)), consistent with gain of function. The I(NaP) increase was inhibited by dialysis of the cytoplasm, consistent with a modulation. Therefore, as shown by the computational model, T1174S could in some conditions induce overall loss of function, and in others gain of function; Q1489K induced gain of function in all the conditions. SIGNIFICANCE: Modulation of the properties of T1174S can lead to a switch between overall gain and loss of function, consistent with a switch between promigraine end epileptogenic effect and, thus, with coexistence of epileptic and FHM phenotypes in the same family. These findings may help to shed light on the complex genotype-phenotype relationship of SCN1A mutations.
Assuntos
Enxaqueca com Aura/complicações , Enxaqueca com Aura/genética , Mutação/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Convulsões/complicações , Convulsões/genética , Adolescente , Adulto , Linhagem Celular Transformada , Simulação por Computador , Análise Mutacional de DNA , Estimulação Elétrica , Feminino , Humanos , Itália , Masculino , Potenciais da Membrana/genética , Potenciais da Membrana/fisiologia , Pessoa de Meia-Idade , Modelos Moleculares , Técnicas de Patch-Clamp , Fenótipo , Serina/genética , Treonina/genética , Adulto JovemRESUMO
Heterozygous mutations of PRRT2, which encodes proline-rich transmembrane protein 2, are associated with heterogeneous phenotypes including benign familial infantile seizures (BFIS), or familial paroxysmal kinesigenic dystonia (PKD). We report a consanguineous Italian family with BFIS/PKD phenotype that contained 14 living members with 6 affected individuals (four men, ranging in age from 6-44 years). We identified the reported c.649dupC (p.Arg217ProfsX8) mutation of PRRT2 gene that cosegregated with the disease and was not observed in 100 controls of matched ancestry. Four patients with BFIS phenotype were heterozygous for this mutation, including the consanguineous parents of the two affected brothers with more severe phenotypes of BFIS/PKD--mental retardation, episodic ataxia, and absences--who were the only individuals to carry a homozygous c.649dupC mutation. This family provides strong evidence that homozygous PRRT2 mutations give rise to more severe clinical disease of mental retardation, episodic ataxia, and absences, and, thus, enlarges the clinical spectrum related to PRRT2 mutations. Moreover, it suggests an additive effect of double dose of the genetic mutation and underscores the complexity of the phenotypic consequences of mutations in this gene.
Assuntos
Ataxia/genética , Coreia/genética , Epilepsia Neonatal Benigna/genética , Deficiência Intelectual/genética , Proteínas de Membrana/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Adolescente , Adulto , Ataxia/complicações , Criança , Coreia/complicações , Epilepsia Neonatal Benigna/complicações , Saúde da Família , Feminino , Estudos de Associação Genética , Homozigoto , Humanos , Deficiência Intelectual/complicações , Masculino , Fenótipo , Adulto JovemRESUMO
The dysbindin (dystrobrevin-binding protein 1) gene has been indicated as one of the most important schizophrenia susceptibility genes. Several genetic variations of this gene have been investigated by using an "intermediate phenotype" approach showing a particular detrimental effect on the prefrontal function in schizophrenic patients. However, the nature of dysbindin function within the brains of healthy individuals is poorly understood, in particular as concerns brain anatomy. We examine relationships between a previously implicated three marker C-A-T dysbindin haplotype and regional cortical thickness in a wide population genotyped for risk carriers (n=14) and non-risk carriers (n=93). Surface-based analysis of the cortical mantle showed that the dysbindin haplotype was associated with structural differences in the medial orbitofrontal cortex, where the risk carriers showed the highest cortical thickness values and the non-risk carriers the lowest. Our study extends previous evidence found on schizophrenic patients to the healthy population, demonstrating the influence of dysbindin risk variants on the neuronal architecture of a specific brain region relevant to the neuropathology of schizophrenia.
Assuntos
Proteínas de Transporte/genética , Córtex Cerebral/anatomia & histologia , Adolescente , Adulto , Idoso , Disbindina , Proteínas Associadas à Distrofina , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Esquizofrenia/genética , Adulto JovemRESUMO
Iron overload may lead to neurodegenerative disorders such as Parkinson's disease (PD) and alterations of iron-related genes might be involved in the pathogenesis of this disease. The gene of haemochromatosis (HFE) encodes the HFE protein which interacts with the transferrin receptor (TFR), lowering its affinity for iron-bound transferrin (TF). We examined four known polymorphisms, C282Y and H63D in the HFE gene, G258S in the TF gene and S82G in the TFR gene, in 181 sporadic PD patients and 180 controls from Southern Italy to investigate their possible role in susceptibility to PD. No significant differences were found in genotype and allele frequencies between PD and controls for all the polymorphisms studied, suggesting that these variants do not contribute significantly to the risk of PD.
Assuntos
Estudos de Associação Genética/métodos , Antígenos de Histocompatibilidade Classe I/genética , Proteínas de Membrana/genética , Doença de Parkinson/genética , Polimorfismo Genético/genética , Receptores da Transferrina/genética , Transferrina/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Proteína da Hemocromatose , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/epidemiologia , Doença de Parkinson/metabolismo , Transferrina/metabolismoRESUMO
The major component of Lewy Bodies (LB), the pathological hallmark of Parkinson's disease (PD) is α-synuclein, most prominently phosphorylated at serine 129. G-protein coupled receptor kinase 5 (GRK5) has been reported to phosphorylate α-synuclein in vitro, enhancing the α-synuclein toxicity to dopaminergic neurons in Drosophila model. Moreover, GRK5 was found in LBs from brain of PD patients. A genetic association study performed in the Japanese population revealed haplotypic association of the GRK5 gene with susceptibility to sporadic PD. We aimed at investigating whether four polymorphisms within the GRK5 gene (rs871196, rs2420616, rs7069375, rs4752293) could represent a risk factor for sporadic PD in Southern Italy. We genotyped 446 patients with PD and 450 controls for these markers and did not find any significant association with the disease at allelic, genotypic and haplotypic level. Our results indicate that the GRK5 gene does not confer risk to sporadic PD in our sample from Southern Italy.
Assuntos
Quinase 5 de Receptor Acoplado a Proteína G/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Doença de Parkinson/enzimologia , Doença de Parkinson/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
The CACNA1A gene codes for the alpha(1A) pore-forming subunit of Ca(2+) voltage-gated Cav2.1 channels. CACNA1A mutations are responsible for Familial Hemiplegic Migraine (FHM) type 1, Episodic Ataxia (EA) type 2 and Spinocerebellar Ataxia type 6. The structure of the human gene includes, at present, 49 exons; however almost nothing is known about the 5' regulatory region, and there is now evidence suggesting the presence of additional exons at the 3' of the gene. The 892 bp fragment upstream of exon 1 and its deletion mutants were characterised for their transcriptional activity by using luciferase as a reporter gene. The 3' region was analysed by Rapid Amplification of the cDNA 3' End. Both regions were screened for mutations in a series of FHM and EA patients by SSCP and sequencing. At the 5' end of the gene a minimal promoter region was identified within the first 497 bp from ATG. By screening a larger fragment for mutations, the 5 bp deletion (g.-757_-753delCTTTC) was identified in a FHM patient. The deletion significantly increased the transcriptional activity, most likely due to the removal of half a turn of the DNA helix, changing the orientation of downstream binding sites for transcriptional factors. At the 3' end of the gene a new exon 48, followed by a strong poly-A signal, was identified as well as a new splice variant. The 5 bp insertion (g.38429_38430insCTTTT) in this exon was found in an EA patient. The two new regions can open the way for the study of human CACNA1A gene expression regulation and can be sites of mutations associated with FHM or EA phenotypes.
Assuntos
Ataxia/genética , Canais de Cálcio/genética , Éxons/genética , Enxaqueca com Aura/genética , Deleção de Sequência/genética , Análise de Variância , Ataxia/sangue , Linhagem Celular Tumoral , Biologia Computacional/métodos , Análise Mutacional de DNA , Humanos , Itália , Enxaqueca com Aura/sangue , Dados de Sequência Molecular , Neuroblastoma/metabolismo , FenótipoRESUMO
Myocardial (123)Metaiodobenzylguanidine (MIBG) enables the assessment of postganglionic sympathetic cardiac innervation. MIBG uptake is decreased in nearly all patients with Parkinson's disease (PD). Our objective was to evaluate MIBG uptake in patients with genetic PD. We investigated MIBG uptake in 14 patients with PD associated with mutations in different genes (Parkin, DJ-1, PINK1, and leucine-rich repeat kinase 2 -LRRK2), in 15 patients with idiopathic PD, and 10 control subjects. The myocardial MIGB uptake was preserved in 3 of the 4 Parkin-associated Parkinsonisms, in 1 of the 2 patients with DJ-1 mutations, in 1 of the 2 brothers with PINK1 mutations, in 3 of the 6 unrelated patients with Gly2019Ser mutation in the LRRK2 gene, whereas it was impaired in all patients with idiopathic PD. MIBG was preserved in all control subjects. Our study shows that myocardial MIGB uptake was normal in 8 of 14 patients with genetic PD, suggesting that cardiac sympathetic denervation occurs less frequently in genetic PD than in idiopathic PD. Our findings also demonstrate that MIGB uptake has a heterogeneous pattern in genetic PD, because it was differently impaired in patients with different mutations in the same gene or with the same gene mutation.
Assuntos
3-Iodobenzilguanidina/farmacocinética , Miocárdio/metabolismo , Doença de Parkinson/diagnóstico , Doença de Parkinson/genética , Transtornos Parkinsonianos/diagnóstico , Transtornos Parkinsonianos/genética , Mutação Puntual/genética , Compostos Radiofarmacêuticos/farmacocinética , Adulto , Análise Mutacional de DNA , Diagnóstico Diferencial , Feminino , Resposta Galvânica da Pele/fisiologia , Genótipo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/sangue , Peptídeos e Proteínas de Sinalização Intracelular/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Masculino , Pessoa de Meia-Idade , Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/epidemiologia , Proteínas Oncogênicas/sangue , Proteínas Oncogênicas/genética , Doença de Parkinson/epidemiologia , Transtornos Parkinsonianos/epidemiologia , Regiões Promotoras Genéticas , Proteína Desglicase DJ-1 , Proteínas Quinases/sangue , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases/sangue , Proteínas Serina-Treonina Quinases/genética , Índice de Gravidade de Doença , Inquéritos e Questionários , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Ubiquitina-Proteína Ligases/sangue , Ubiquitina-Proteína Ligases/genéticaRESUMO
Recent studies have reported an association between the glucocerebrosidase (GBA) gene and Parkinson's disease (PD). To elucidate the role of this gene in our population, we screened 395 PD patients and 483 controls from southern Italy for the N370S and the L444P mutations. We found 11 patients (2.8%) carrying a heterozygous mutant GBA allele, whereas only one control subject (0.2%) had a heterozygous substitution (P = 0.0018). These results strongly suggest that Italian carriers of a GBA mutation have an increased risk of developing PD.
Assuntos
Predisposição Genética para Doença , Glucosilceramidase/genética , Mutação/genética , Doença de Parkinson/genética , Idoso , Asparagina/genética , Análise Mutacional de DNA , Feminino , Frequência do Gene , Genótipo , Humanos , Itália/epidemiologia , Leucina/genética , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/epidemiologia , Prolina/genética , Serina/genéticaAssuntos
Arginina/genética , Proteínas de Choque Térmico/genética , Histidina/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Espasticidade Muscular/diagnóstico , Espasticidade Muscular/genética , Mutação de Sentido Incorreto/genética , Atrofia Óptica/diagnóstico , Atrofia Óptica/genética , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/genética , Adulto , Feminino , Humanos , Itália , SicíliaRESUMO
Herein we first describe a novel homozygous single nucleotide deletion in PINK1 exon 4 (889delG) which results in a loss of kinase domain on the PINK1 protein (D297fsX318). This mutation was identified in two brothers with early-onset Parkinson disease (EOPD) from a Sicilian consanguineous family. Of note, while one of the two patients developed mental deterioration and psychiatric problems, the other showed no cognitive decline. The present study supports the view that PINK1 is a pathogenic gene in some Italian families with EOPD and contributes to define the PINK1-associated phenotype.
Assuntos
Doença de Parkinson/genética , Proteínas Quinases/genética , Idade de Início , Idoso , Sequência de Aminoácidos , Antiparkinsonianos/uso terapêutico , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/psicologia , Éxons/genética , Deleção de Genes , Genótipo , Humanos , Levodopa/uso terapêutico , Masculino , Dados de Sequência Molecular , Mutação , Doença de Parkinson/psicologia , Linhagem , FenótipoAssuntos
Saúde da Família , Repetições de Microssatélites/genética , Epilepsias Mioclônicas Progressivas/genética , Proteínas do Tecido Nervoso/genética , Polimorfismo de Nucleotídeo Único/genética , Povo Asiático , Feminino , Estudos de Associação Genética , Haplótipos , Humanos , Itália , MasculinoRESUMO
PURPOSE: Mutations in the genes encoding the alfa(2), alfa(4) and beta(2) subunits of the neuronal nicotinic acetylcholine receptor (nAChR) play a causative role in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Moreover, variations in the promoter of the corticotropic-releasing hormone gene (CRH) were also associated with ADNFLE. Here, we investigated whether nine brain-expressed genes (CHRNA2, CHRNA3, CHRNA4, CHRNA5, CHRNA6, CHRNA7, CHRNB2, CHRNB3, CHRNB4), encoding distinct nAChR subunits, and CRH are associated with the disease in three distinct ADNFLE families from Southern Italy. METHODS: There were 14 living affected individuals (9 women), ranging in age from 14 to 57 years, pertaining to three unrelated families. Age at onset of seizures clustered around 9 years of age (range from 7 and 16 years, mean: 9.1 years+/-3.8). All affected individuals manifested nocturnal partial seizures of frontal lobe origin, which were well controlled by medications. Exon 5 of CHRNA4 and CHRNB2 genes, harboring all the known mutations, was sequenced in the probands. Then, we performed a linkage study on 13 affected and 26 non-affected individuals belonging to the three families with microsatellite markers and an intragenic polymorphisms encompassing the chromosome localization of the nAChR subunit genes and of the CRH gene. RESULTS: Mutational and linkage analyses allowed us to exclude the involvement of all known nAChR subunit genes and of the CRH gene in ADNFLE in our families. CONCLUSION: Our results further illustrate the considerable genetic heterogeneity for such a syndrome, despite the quite homogeneous clinical picture. It is therefore reasonable to hypothesize that at least another gene not belonging to the nAChR gene family, in addition to CRH, is involved in the pathogenesis of ADNFLE.
Assuntos
Hormônio Liberador da Corticotropina/genética , Epilepsia do Lobo Frontal/genética , Receptores Nicotínicos/genética , Éxons , Feminino , Heterogeneidade Genética , Ligação Genética , Humanos , Masculino , Mutação , Linhagem , Transtornos do Sono-Vigília/genéticaRESUMO
BACKGROUND: Several factors, both clinical and genetic, may account for the risk of developing levodopa-induced peak-dose dyskinesias (PDD) in patients with Parkinson disease, but it is unclear how these factors interact for modulating the individual susceptibility for PDD. OBJECTIVE: To examine clinical and genetic risk factors for determining individual susceptibility of PDD in patients with Parkinson disease. DESIGN: Cohort study. SETTING: Referral center for Parkinson disease in Calabria, southern Italy. Patients Two hundred fifty patients with Parkinson disease were screened for the presence or absence of PDD following a short-term levodopa administration, and 215 subjects were available for further evaluations, including genotypic analysis of the CA dinucleotide short tandem repeat (CAn-STR) polymorphism located in the dopamine receptor D2 gene (DRD2). RESULTS: One hundred five patients (48.8%) exhibited PDD following short-term levodopa administration, and 110 patients (51.2%) did not. Multivariate logistic regression analysis showed that independent predictors for the occurrence of PDD were female sex, earlier age at onset of Parkinson disease, longer duration of treatment, and higher dose of levodopa. Genetic factors related to the DRD2 CAn-STR polymorphism were not independent predictors for PDD in the total population, but they had a strong protective effect on the appearance of PDD when the multivariate analysis was performed in men (odds ratio, 0.34 [95% confidence interval, 0.14-0.84]). In women, a genetic protective effect on PDD was not evident. CONCLUSIONS: Risk factors for PDD, both clinical and genetic, act in different ways for men and women. Genetic factors related to the DRD2 polymorphic status have a protective effect on PDD development in men but not in women. A female sex-related effect for the risk of PDD may be so strong that it overcomes any protective effect due to genetic factors.
Assuntos
Discinesia Induzida por Medicamentos/genética , Predisposição Genética para Doença/genética , Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Caracteres Sexuais , Idade de Início , Idoso , Antiparkinsonianos/efeitos adversos , Estudos de Coortes , Análise Mutacional de DNA , Expansão das Repetições de DNA/genética , Relação Dose-Resposta a Droga , Discinesia Induzida por Medicamentos/metabolismo , Discinesia Induzida por Medicamentos/fisiopatologia , Feminino , Testes Genéticos , Genótipo , Humanos , Masculino , Análise Multivariada , Polimorfismo Genético/genética , Valor Preditivo dos Testes , Receptores de Dopamina D2/genéticaRESUMO
BACKGROUND: Primary familial brain calcification (PFBC) is a rare neurodegenerative disease characterized by bilateral calcifications mostly located in the basal ganglia and in the thalami, cerebellum and subcortical white matter. Clinical manifestations of this disease include a large spectrum of movement disorders and neuropsychiatric disturbances. PFBC is genetically heterogeneous and typically transmitted in an autosomal dominant fashion. Three causative genes have been reported: SLC20A2, PDGFRB and PDGFB. OBJECTIVE: We screened three PFBC Italian families for mutations in the SLC20A2, PDGFRB and PDGFB genes. METHODS: Phenotypic data were obtained by neurologic examination, CT scan and magnetic resonance imaging. Mutation screening of SLC20A2, PDGFRB and PDGFB was performed by sequencing. RESULTS: We identified a new heterozygous deletion c.21_21delG (p.L7Ffs*10) in SLC20A2 gene in one of these families. No mutations were detected in the other two families. CONCLUSIONS: Our data confirm that mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification.
Assuntos
Doenças dos Gânglios da Base/genética , Calcinose/genética , Doenças Neurodegenerativas/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/genética , Sequência de Aminoácidos , Sequência de Bases , Análise Mutacional de DNA , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Deleção de SequênciaRESUMO
The objective of our study was to investigate the association of two single nucleotide polymorphisms (SNPs) with genetic risk of dementia. In 212 patients with Parkinson's disease (PD), we investigated two polymorphisms within the G-protein coupled receptor kinase 5 (GRK5) gene (rs2420616, rs4752293) to determine a possible risk factor for dementia. We identified two alleles most significantly present in PD patients with dementia: G and T alleles. We also identified risk haplotypes: GC, and AT. We demonstrated that the SNPs and the related haplotypes could play a central role in predisposing PD patients to cognitive impairment.
Assuntos
Alelos , Transtornos Cognitivos/genética , Demência/genética , Quinase 5 de Receptor Acoplado a Proteína G/genética , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único , Idoso , Transtornos Cognitivos/etiologia , Demência/etiologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Fatores de RiscoRESUMO
PURPOSE: Mutations in PCDH19, encoding protocadherin 19 on chromosome X, cause familial epilepsy and mental retardation limited to females or Dravet-like syndrome. We wished to explore the causative role of PCDH19 gene (Xq22) in female patients with epilepsy, from Southern Italy. METHODS: Direct sequencing of PCDH19 gene was conducted in 31 unrelated female patients with early onset (<1 year of age) epilepsy and a wide spectrum of phenotypes including febrile seizures, focal and generalized forms, with either sporadic or familial distribution. RESULTS: We identified two de novo heterozygous novel mutations of PCDH19 gene (p.Arg550Pro, Ile508ProfsX59) in two of 31 unrelated female patients. We also identified a novel silent mutation p.Ser856=. CONCLUSIONS: The present findings confirm that PCDH19 is a major causative gene for infantile onset familial or sporadic epilepsy in female patients with or without mental retardation.
Assuntos
Caderinas/genética , Epilepsia/genética , Mutação/genética , Criança , Análise Mutacional de DNA , Epilepsia/complicações , Feminino , Humanos , Itália , Transtornos Mentais/complicações , Transtornos Mentais/genética , ProtocaderinasRESUMO
There is evidence that male subjects with a clinical picture of action tremor, Parkinsonism, and cerebellar ataxia may have Fragile X premutations (FRAXA). We analyzed FRAXA and FRAXE triplet repeats in 203 male subjects with Parkinson's disease (PD) and 370 healthy controls. No full mutations or premutations at the FRAXA and FRAXE loci were found in the subjects with PD or in the controls. FRAXA allele distribution was similar in patients and controls. FRAXE intermediate alleles (31-60 repeats CCG) were found in 13 of 203 (6.4%) subjects with PD and in only one of the 370 (0.27%) healthy controls (P < 0.001), thus indicating that these relatively large alleles may be associated with PD.