Role of LRRK2 and SNCA in autosomal dominant Parkinson's disease in Turkey.

Mutations in the LRRK2 and alpha-synuclein (SNCA) genes are well-established causes of autosomal dominant Parkinson's disease (PD). However, their frequency differs widely between ethnic groups. Only three studies have screened all coding regions of LRRK2 and SNCA in European samples so far. In Turkey, the role of LRRK2 in Parkinson's disease has been studied fragmentarily, and the incidence of SNCA copy number variations is unknown. The purpose of this study is to determine the frequency of LRRK2 and SNCA mutations in autosomal dominant PD in Turkey. We performed Sanger sequencing of all coding LRRK2 and SNCA exons in a sample of 91 patients with Parkinsonism. Copy number variations in SNCA, PRKN, PINK1, DJ1 and ATP13A2 were assessed using the MLPA method. All patients had a positive family history compatible with autosomal dominant inheritance. Known mutations in LRRK2 and SNCA were found in 3.3% of cases: one patient harbored the LRRK2 G2019S mutation, and two patients carried a SNCA gene duplication. Furthermore, we found a heterozygous deletion of PRKN exon 2 in one patient, and four rare coding variants of unknown significance (LRRK2: A211V, R1067Q, T2494I; SNCA: T72T). Genetic testing in one affected family identified the LRRK2 R1067Q variant as a possibly pathogenic substitution. Point mutations in LRRK2 and SNCA are a rare cause of autosomal dominant PD in Turkey. However, copy number variations should be considered. The unclassified variants, especially LRRK2 R1067Q, demand further investigation.

Kessler C ，Atasu B ，Hanagasi H ，Simón-Sánchez J ，Hauser AK ，Pak M ，Bilgic B ，Erginel-Unaltuna N ，Gurvit H ，Gasser T ，Lohmann E ... -  《-》

Autosomal dominant Parkinson's disease: Incidence of mutations in LRRK2, SNCA, VPS35 and GBA genes in Brazil.

Amongst Parkinson's disease (PD) genetic factors, mutations in LRRK2, SNCA, VPS35 and GBA genes are recognized causes of PD. Nonetheless, few genetic screenings have been conducted in families with a history of PD consistent with autosomal dominant inheritance (ADPD), and their relevance to the etiology of PD has been poorly explored in Latin American populations, such as the Brazilian one, with a high degree of admixture. In order to assess the contribution of specific mutations in LRRK2, SNCA, VPS35 and GBA genes to ADPD in Brazil, we conducted the first molecular evaluation in a cohort of 141 index cases from families with ADPD. Genomic DNA was isolated from peripheral blood or saliva, and the molecular analysis was performed by TaqMan allelic discrimination assays or bidirectional sequencing. Heterozygous mutations in LRRK2 and GBA genes were identified in 10 (7.0%) probands, and all presented typical signs of classical PD. No mutations were found in SNCA or VPS35 genes. Our findings in a representative series of index cases from families with ADPD emphasize the important contribution of LRRK2 G2019S and GBA (L444P and N370S) mutations to parkinsonism in Brazilian families. The absence of mutations in VPS35 and SNCA genes reveals that they are uncommon causes of PD in Brazil, corroborating previous studies that also failed to detect these genetic variants in PD patients from other populations. Recent discoveries of novel causative genes of autosomal dominant forms of PD expand the investigative possibilities and should be targeted on future studies.

Abreu GM ，Valença DC ，Campos M Júnior ，da Silva CP ，Pereira JS ，Araujo Leite MA ，Rosso AL ，Nicaretta DH ，Vasconcellos LF ，da Silva DJ ，Della Coletta MV ，Dos Santos JM ，Gonçalves AP ，Santos-Rebouças CB ，Pimentel MM ... -  《-》

Screening for SNCA and LRRK2 mutations in Greek sporadic and autosomal dominant Parkinson's disease: identification of two novel LRRK2 variants.

Xiromerisiou G ，Hadjigeorgiou GM ，Gourbali V ，Johnson J ，Papakonstantinou I ，Papadimitriou A ，Singleton AB ... -  《-》

Mutation analysis of the PARKIN, PINK1, DJ1, and SNCA genes in Turkish early-onset Parkinson's patients and genotype-phenotype correlations.

Variations in PARK genes (PRKN, PINK1, DJ-1, and SNCA) cause early-onset Parkinson's disease (EOPD) in different populations. In the current study, we aimed to evaluate the frequencies of variations in PARK genes and the effects of these variations on the phenotypes of Turkish EOPD patients. All coding regions and exon-intron boundaries of the PRKN, PINK1, DJ-1, and SNCA genes were screened by heteroduplex analysis followed by direct sequencing of the detected variants in 50 Turkish EOPD patients. These variants were evaluated using SIFT, PolyPhen, HSF, and LOVD web-based programs. The frequency of EOPD-associated variations in the PRKN gene was 34%. Among these variations, p.A82E in exon 3 and p.Q409X in exon 11 was determined to be pathogenic. We also defined previously unknown cryptic variations, including c.872-35 G>A and c.872-28T>G in exon 8 of PRKN and c.252+30 T>G and c.322+4 A>G in exons 4 and 5 of DJ1, respectively, that were associated with EOPD. Although no significant association was observed between the PARK gene mutations and clinical features (P>0.05), the alterations were related to the clinical symptoms in each patient. An increasing number of studies report that PRKN, PINK1, DJ1 and SNCA mutations are associated with early-onset Parkinson's disease; however, a limited number of studies have been conducted in Turkey. Additionally, our study is the first to evaluate the frequency of SNCA mutations in a Turkish population. The aim of this study was determine the frequency distributions of the PRKN, PINK1, DJ1, and SNCA gene mutations and to analyze the relationships between these genetic variations and the clinical phenotype of EOPD in Turkish patients.

Erer S ，Egeli U ，Zarifoglu M ，Tezcan G ，Cecener G ，Tunca B ，Ak S ，Demirdogen E ，Kenangil G ，Kaleagası H ，Dogu O ，Saka E ，Elibol B ... -  《-》

Resequencing analysis of five Mendelian genes and the top genes from genome-wide association studies in Parkinson's Disease.

Benitez BA ，Davis AA ，Jin SC ，Ibanez L ，Ortega-Cubero S ，Pastor P ，Choi J ，Cooper B ，Perlmutter JS ，Cruchaga C ... -  《Molecular Neurodegeneration》