A Novel SNCA A30G Mutation Causes Familial Parkinsonʼs Disease

Abstract

A BS TRACT: Background: The SNCA gene encoding α-synuclein (αSyn) is the first gene identified to cause autosomal-dominant Parkinsonʼs disease (PD). Objective: We report the identification of a novel heterozygous A30G mutation of the SNCA gene in familial PD and describe clinical features of affected patients, genetic findings, and functional consequences. Methods: Whole exome sequencing was performed in the discovery family proband. Restriction digestion with Bbvl was used to screen SNCA A30G in two validation cohorts. The Greek cohort included 177 familial PD probands, 109 sporadic PD cases, and 377 neurologically healthy controls. The German cohort included 136 familial PD probands, 380 sporadic PD cases, and 116 neurologically healthy controls. We also conducted haplotype analysis using 13 common single nucleotide variants around A30G to determine the possibility of a founder effect for A30G. We then used biophysical methods to characterize A30G αSyn.Results: We identified a novel SNCA A30G (GRCh37, Chr4:90756730, c.89 C>G) mutation that co-segregated with the disease in five affected individuals of three Greek families and was absent from controls. A founder effect was strongly suggested by haplotype analysis. The A30G mutation had a local effect on the intrinsically disordered structure of αSyn, slightly perturbed membrane binding, and promoted fibril formation. Conclusion:Based on the identification of A30G cosegregating with the disease in three families, the absence of the mutation in controls and population databases, and the observed functional effects, we propose SNCA A30G as a novel causative mutation for familial PD.

Alpha-synuclein research: defining strategic moves in the battle against Parkinson’s disease

“…Independent A53T mutations have been identified in Korean 4 and Swedish 5 patients. Seven other mutations in the SNCA gene have been described for which co-segregation in autosomal-dominant families supports pathogenicity-A30P 6 , E46K 7 , G51D 8 , H50Q 9 , A53V 10 , A53E 11 , and A30G 12 . Today it is undisputed that at least some of these point mutations cause PD with high penetrance, even though the total number of mutation carriers is rather low and not in all of the genetic evidence of co-segregation is unequivocal.…”

Genetic Analysis and Literature Review of SNCA Variants in Parkinson's Disease

“…Multiple susceptibility genes, diseasecausing genes, and genetic risk loci attributed to PD have been identified (Hernandez et al, 2016;Liu and Le, 2020). Intriguingly, some pleomorphic risk loci overlap with the known causative genes of monogenic PD, such as SNCA, glucosylceramidase beta (GBA), leucine rich repeat kinase 2 (LRRK2), and vacuolar protein sorting 13 homolog C (VPS13C) (Singleton and Hardy, 2011;Nalls et al, 2019;Blauwendraat et al, 2020 (Polymeropoulos et al, 1997;Youn et al, 2019;Chen et al, 2020;Zhao et al, 2020;Brás et al, 2021;Liu et al, 2021). The CNVs of the SNCA locus were discovered in an Iowan kindred for the first time in 2003 (Singleton et al, 2003).…”

Alpha-Synuclein and Lipids: The Elephant in the Room?

“…The α-syn protein is encoded by the Non-A4 Component Of Amyloid Precursor ( SNCA ) gene that is located at the PARK1/4 locus on chromosome 4q21 and consists of six protein coding exons [ 5 , 6 , 7 ]. While PD is mainly sporadic, several deleterious or potentially deleterious mutations in this gene (A18T, A29S, A30G, A30P, E46K, H50Q, G51D, A53E, A53T, and A53V) have been linked to familial parkinsonism [ 8 , 9 , 10 , 11 ] ( Figure 1 a). Further evidence, including triplication [ 12 ] and duplication of the SNCA gene locus [ 13 , 14 ], demonstrates that the sole overexpression of α-syn can lead to the disease.…”