Exon Dosage Variations in Brazilian Patients with Parkinson’s Disease: Analysis ofSNCA,PARKIN,PINK1andDJ-1Genes

Moura, Karla Cristina Vasconcelos; Campos, Mário; Rosso, Ana Lucia; Nicaretta, Denise Hack; Pereira, Joäo Santos; Silva, Delson José; Santos-Rebouças, Cíntia Barros; Pimentel, Márcia Mattos Gonçalves

doi:10.1155/2012/218642

Cited by 14 publications

(16 citation statements)

References 25 publications

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“…This corroborates the data presented by Moura et al 14 , who conducted research on Brazilian populations and quantified the SNCA gene mutations without finding any alterations. SNCA multiplications have been implicated in autosomal dominant forms of PD since 2003 15 .…”

Section: Discussionsupporting

confidence: 92%

“…Remarkably, further Brazilian studies found no SNCA-A53T mutation in PD patients 14,18,19 . Furthermore, other genes re1ated to PD, such as APOE, GSTs and LRRK2 (PARK8), also showed no difference between patients and controls in this population 20,21,22,23 .…”

Section: Discussionmentioning

confidence: 88%

“…However, these discrepancies seem to have little relevance, considering the absence of said mutation in both groups, which seems to be different in the Brazilian population 14,18,19 . Additionally, individuals remained in the control group, regardless of the matching pair analysis with patients, which enabled a larger number of individuals to perform comparative analysis.…”

Section: Discussionmentioning

confidence: 94%

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Alpha-synuclein A53T mutation is not frequent on a sample of Brazilian Parkinson’s disease patients

Longo

Pinhel

Gregório

et al. 2015

Arq. Neuro-Psiquiatr.

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Parkinson's disease (PD) is one of the major degenerative disorders, affecting 2% of the population over 65 years and up to 4% in people over 85 years 1 . In Brazil, statistics show that the incidence of PD amounts to 150/200 cases per 100,000 inhabitants 2 . Most cases of PD are idiopathic 3 . However, in approximately 5%-10% of the cases, there is a genetic component with both dominant and recessive inheritance patterns 3 . The chromosomal loci linked to the familial forms of PD are termed PARK1-13. These loci include six autosomal dominant genes [PARK 1or PARK 4 (alpha synuclein -SNCA), PARK 3 (Lewy bodies), PARK 5 (ubiquitin carboxyl-terminal esterase L1 -UCHL1), PARK 8 (leucine-rich repeat kinase 2 -LRRK2) and PARK13 (HTRA serine peptidase 2 -HTRA2)], 4 recessives genes [PARK 2 ABSTRACT Introduction:The pathogenesis of Parkinson's disease (PD) involves both genetic susceptibility and environmental factors, with focus on the mutation in the alpha-synuclein gene (SNCA). Objective: To analyse the polymorphism SNCA-A53T in patients with familial PD (FPD) and sporadic PD (SPD). Method: A total of 294 individuals were studied, regardless of sex and with mixed ethnicity. The study group with 154 patients with PD, and the control group included 140 individuals without PD. The genotyping of SNCA-A53T was performed by PCR/RFLP. Significance level was p < 0.05. Results: Among all patients, 37 (24%) had FPD and 117 (75.9%) had SPD. The absence of SNCA-A53T mutation was observed in all individuals. Conclusion: SPD is notably observed in patients. However, the SNCA-A53T mutation was absent in all individuals, which does not differ controls from patients. This fact should be confirmed in a Brazilian study case with a more numerous and older population. Keywords:Parkinson's disease, alpha-synuclein, mutation. RESUMO Introdução:A patogênese da doença de Parkinson (DP) envolve fatores ambientais e suscetibilidade genética, destacando-se a mutação de alfa-sinucleína (SNCA.) Objetivos: Analisar a variante genética SNCA-A53T em pacientes com DP familiar (DPF) e DP esporádica (DPE). Método: Foram estudados 294 indivíduos, independente de sexo, com etnia miscigenada, sendo 154 com DP e 140 sem a doença (grupo controle). A genotipagem de SNCA-A53T foi realizada por PCR/RFLP. Nível de significância para p < 0,05. Resultados: Entre os pacientes, 37(24%) tinham DPF e 117 (75,9%) DPE. A ausência da mutação SNCA-A53T em todos os indivíduos. Conclusão: DPE é destacada entre os pacientes, no entanto a mutação SNCA-A53T ausente em todos os indivíduos, não diferenciando os grupo controle e pacientes, o que deve ser confirmado em população brasileira, considerando uma ampla casuística, além da ancestralidade.Palavras-chave: doença de Parkinson, alfa sinucleína, mutação.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 94%

See 1 more Smart Citation

Alpha-synuclein A53T mutation is not frequent on a sample of Brazilian Parkinson’s disease patients

Longo

Pinhel

Gregório

et al. 2015

Arq. Neuro-Psiquiatr.

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“…For this reason, more than 200 putative pathogenic mutations have been reported worldwide, affecting numerous ethnic populations [33,35,59,[64][65][66][67][68][69][70][71][72][73][74][75][76][77]. The PARK2 mutation spectrum includes homozygous or compound heterozygous missense and nonsense point mutations, as well as several exon rearrangements (both duplications and deletions) involving all 12 exons and the promoter region.…”

Section: Park2mentioning

confidence: 99%

“…It is likely that the deletion results from an unequal crossing-over between these two sequences. Further heterozygous deletions involving exons 1, 3-8 and exon 7 have been described in familial or sporadic cases of early-onset PD [72,93,94].…”

Section: Pink1mentioning

confidence: 99%

Genetics of Parkinson’s Disease: The Role of Copy Number Variations

Cognata¹,

D’Agata²,

Cavalcanti³

et al. 2016

Challenges in Parkinson's Disease

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Parkinson's disease (PD), the second most common progressive neurodegenerative disorder, was long believed to be a non-genetic sporadic origin syndrome. The identification of distinct genetic loci responsible for rare Mendelian forms of PD has represented a revolutionary breakthrough, allowing to discover novel mechanisms underlying this debilitating still incurable condition. Along with single-nucleotide polymorphisms (SNPs), other kinds of DNA molecular defects have emerged as significant disease-causing mutations, including large chromosomic structural rearrangements and copy number variations (CNVs). Due to their size variability and to the different sensitivity and resolution of detection methodologies, CNVs constitute a particular challenge in genetic studies and the pathogenetic or susceptibility impact of specific CNVs on PD is currently under debate. In this chapter, we will review the current literature and bioinformatic data describing the involvement of CNVs on PD pathobiology. We will discuss the recently highlighted role of PARK2 heterozygous CNVs, the possible common founder effects of PD gene rearrangements and the importance to map genetic breakpoints. We will also add a summary about the current available molecular methods and bioinformatics web resources to detect and interpret CNVs. Assessing the global genome-wide burden of large CNVs and elucidating the role of de novo rare structural variants on PD may reveal new candidate genes and consequently ameliorate diagnosis and counselling of mutations carriers.

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Genetic mutations in early‐onset Parkinson's disease Mexican patients: Molecular testing implications

Monroy-Jaramillo

Guerrero-Camacho

Rodríguez-Violante

et al. 2014

American J of Med Genetics Pt B

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Mutations in PARK2, PINK1, and DJ-1 have been associated with autosomal recessive early-onset Parkinson's disease. Here, we report the prevalence of sequence and structural mutations in these three main recessive genes in Mexican Mestizo patients. The complete sequences of these three genes were analyzed by homo/heteroduplex DNA formation and direct sequencing; exon dosage was determined by multiplex ligation-dependent probe amplification and real-time PCR in 127 patients belonging to 122 families and 120 healthy Mexican Mestizo controls. All individuals had been previously screened for the three most common LRRK2 mutations. The presence of two mutations in compound heterozygous or homozygous genotypes was found in 16 unrelated patients, 10 had mutations in PARK2, six in PINK1, and none in DJ-1. Two PARK2-PINK1 and one PARK2-LRRK2 digenic cases were observed. Novel mutations were identified in PARK2 and PINK1 genes, including PINK1 duplication for the first time. Exon dosage deletions were the most frequent mutations in PARK2 (mainly in exons 9 and 12), followed by those in PINK1. The high prevalence of heterozygous mutations in PARK2 (12.3%) and the novel heterozygous and homozygous point mutations in PINK1 observed in familial and sporadic cases from various states of Mexico support the concept that single heterozygous mutations in recessive Parkinson's disease genes play a pathogenic role. These data have important implications for genetic counseling of Mexican Mestizo patients with early-onset Parkinson's disease. The presence of digenic inheritance underscores the importance of studying several genes in this disease. A step-ordered strategy for molecular diagnosis is proposed.

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Exon Dosage Variations in Brazilian Patients with Parkinson’s Disease: Analysis ofSNCA,PARKIN,PINK1andDJ-1Genes

Cited by 14 publications

References 25 publications

Alpha-synuclein A53T mutation is not frequent on a sample of Brazilian Parkinson’s disease patients

Alpha-synuclein A53T mutation is not frequent on a sample of Brazilian Parkinson’s disease patients

Genetics of Parkinson’s Disease: The Role of Copy Number Variations

Genetic mutations in early‐onset Parkinson's disease Mexican patients: Molecular testing implications

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