A new alpha-synuclein missense variant (Thr72Met) in two Turkish families with Parkinson's disease

Abstract

Introduction: Missense variants and multiplications of the alpha-synuclein gene (SNCA) are established as rare causes of autosomal dominant forms of Parkinson's Disease (PD). Methods: Two families of Turkish origins with PD were studied; the SNCA coding region was analyzed by Sanger sequencing, and by whole exome sequencing (WES) in the index patient of the first and the second family, respectively. Co-segregation studies and haplotype analysis across the SNCA locus were carried out. Functional studies included in vitro thioflavin-T aggregation assay and in silico structural modelling of the alpha-synuclein (α-syn) protein.Results: We identified a novel heterozygous SNCA variant, c.215C > T (p.Thr72Met), segregating with PD in a total of four members in the two families. A shared haplotype across the SNCA locus was found among variant carriers, suggestive of a common ancestor. We next showed that the Thr72Met α-syn displays enhanced aggregation in-vitro, compared to the wild-type species. In silico analysis of a tetrameric α-syn structural model revealed that Threonine 72 lies in the tetrameric interface, and substitution with the much larger methionine residue could potentially destabilize the tetramer. Conclusion:We present clinical, genetic, and functional data supporting a causative role of the SNCA c.215C > T (p.Thr72Met) variant in familial PD. Testing for this variant in patients with PD, especially of Turkish origin, might detect additional carriers. Further functional analyses might offer new insights into the shared biochemical properties of the PD-causing SNCA missense variants, and how they lead to neurodegeneration.

Updated benchmarking of variant effect predictors using deep mutational scanning

“…We calculated the ROC AUC for every protein with at least 10 pathogenic and 10 putatively benign missense variants. We also supplemented the CALM1 dataset by adding variants from CALM2 and CALM3 , which have identical amino acid sequences, and identified additional pathogenic SNCA variants in the literature (Fevga et al , 2021; Daida et al , 2022; Kapasi et al , 2020).…”

“…Pathogenic variants were primarily obtained from the ClinVar database of clinically relevant variants (August 2022 update) (Landrum et al , 2014) (https://www.ncbi.nlm.nih.gov/clinvar/) and also from HGMD (free version) (Stenson et al , 2003) (https://www.hgmd.cf.ac.uk/ac/index.php). Additional pathogenic variants from SNCA were found though a literature search (Fevga et al , 2021; Daida et al , 2022; Kapasi et al , 2020). Any pathogenic variants present in the gnomAD dataset were removed from the gnomAD set.…”

α‐Synuclein V15A Variant in Familial Parkinson's Disease Exhibits a Weaker Lipid‐Binding Property

“…The subjects in our study and in the Italian family responded well to levodopa, which is similar to A30P cases, of which symptoms are similar to those of sporadic late‐onset PD 47 . These findings suggest that the severity in clinical symptoms of patients with V15A might be intermediate in patients with known SNCA pathogenic mutations, although there is clinical variability in SNCA missense mutations 52 . It is important to study additional cases to clarify the clinical phenotype of V15A.…”

The E46K mutation modulates α-synuclein prion replication in transgenic mice

“…The point mutation is located in the fourth of seven imperfect KTKEGV repeats, which are thought to support α-synuclein’s interactions with lipids [ 47 ]. Until the recent discoveries of the T72M and E83Q mutations [ 13 , 14 ], E46K was the only α-synuclein mutation known to disrupt one of the KTKEGV repeats, suggesting it may exert differing effects on α-synuclein biology and pathogenesis than other PD-causing mutations. Studies investigating the effect of the E46K mutation on α-synuclein fibrillization kinetics found that the amino acid substitution increases the protein’s propensity to fibrillize compared to WT α-synuclein [ 41 ].…”

“…While MSA and LBD patients can present with overlapping motor deficits, MSA patients are typically diagnosed earlier in life (50-60 years old rather than >70 years old) and experience a more rapid disease progression compared to LBD patients [2][3][4]. However, while there are eleven known familial LBD mutations in the gene encoding α-synuclein, SNCA, no mutations have been identified in MSA patients [5][6][7][8][9][10][11][12][13][14][15][16].…”