Márcia M G Pimentel1, Fabíola C Rodrigues2, Marco Antônio A Leite3, Mário Campos Júnior4, Ana Lucia Rosso5, Denise H Nicaretta6, João S Pereira7, Delson José Silva8, Marcus V Della Coletta9, Luiz Felipe R Vasconcellos10, Gabriella M Abreu2, Jussara M Dos Santos2, Cíntia B Santos-Rebouças2. 1. Department of Genetics, Institute of Biology Roberto Alcantara Gomes, State University of Rio de Janeiro, Rio de Janeiro, Brazil. Electronic address: pimentel@uerj.br. 2. Department of Genetics, Institute of Biology Roberto Alcantara Gomes, State University of Rio de Janeiro, Rio de Janeiro, Brazil. 3. Movement Disorders Unit, Division of Neurology, University Hospital Antônio Pedro, Fluminense Federal University, Brazil. 4. Brazil Human Genetics Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil. 5. University Hospital Clementino Fraga Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil. 6. Santa Casa da Misericórdia do Rio de Janeiro, Rio de Janeiro, Brazil. 7. Movement Disorders Section, Neurology Service, Pedro Ernesto University Hospital, State University of Rio de Janeiro, Rio de Janeiro, Brazil. 8. Neuroscience Core, Hospital Clinics, Federal University of Goiás, Brazil; Integrated Neurosciences Institute, Goiás, Brazil. 9. University Hospital Getúlio Vargas, Federal University of Amazonas, Amazonas, Brazil. 10. Institute of Neurology Deolindo Couto, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; Federal Hospital of Servidores do Estado, Rio de Janeiro, Brazil.
Abstract
BACKGROUND: Amongst Parkinson's disease-causing genetic factors, missense mutations and genomic multiplications in the gene encoding α-synuclein are well established causes of the disease, although genetic data in populations with a high degree of admixture, such as the Brazilian one, are still scarce. METHODS: In this study, we conducted a molecular screening of α-synuclein point mutations and copy number variation in the largest cohort of Brazilian patients with Parkinson's disease (n = 549) and also in twelve Portuguese and one Bolivian immigrants. Genomic DNA was isolated from peripheral blood leukocytes or saliva, and the mutational screening was performed by quantitative and qualitative real-time PCR. RESULTS: The only alteration identified was the p.E46K mutation in a 60-year-old man, born in Bolivia, with a familial history of autosomal dominant Parkinson's disease. This is the second family ever reported, in which this rare pathogenic mutation is segregating. The same mutation was firstly described ten years ago in a Spanish family with a neurodegenerative syndrome combining parkinsonism, dementia and visual hallucinations. The clinical condition of our proband reveals a less aggressive phenotype than previously described and reinforces that marked phenotypic heterogeneity is common among patients with Parkinson's disease, even among those carriers sharing the same mutation. CONCLUSION: Our findings add new insight into the preexisting information about α-synuclein p.E46K, improving our understanding about the endophenotypes associated to this mutation and corroborate that missense alterations and multiplications in α-synuclein are uncommon among Brazilian patients with Parkinson's disease.
BACKGROUND: Amongst Parkinson's disease-causing genetic factors, missense mutations and genomic multiplications in the gene encoding α-synuclein are well established causes of the disease, although genetic data in populations with a high degree of admixture, such as the Brazilian one, are still scarce. METHODS: In this study, we conducted a molecular screening of α-synuclein point mutations and copy number variation in the largest cohort of Brazilian patients with Parkinson's disease (n = 549) and also in twelve Portuguese and one Bolivian immigrants. Genomic DNA was isolated from peripheral blood leukocytes or saliva, and the mutational screening was performed by quantitative and qualitative real-time PCR. RESULTS: The only alteration identified was the p.E46K mutation in a 60-year-old man, born in Bolivia, with a familial history of autosomal dominant Parkinson's disease. This is the second family ever reported, in which this rare pathogenic mutation is segregating. The same mutation was firstly described ten years ago in a Spanish family with a neurodegenerative syndrome combining parkinsonism, dementia and visual hallucinations. The clinical condition of our proband reveals a less aggressive phenotype than previously described and reinforces that marked phenotypic heterogeneity is common among patients with Parkinson's disease, even among those carriers sharing the same mutation. CONCLUSION: Our findings add new insight into the preexisting information about α-synuclein p.E46K, improving our understanding about the endophenotypes associated to this mutation and corroborate that missense alterations and multiplications in α-synuclein are uncommon among Brazilian patients with Parkinson's disease.