<p>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 &gt; 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 &gt; 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.</p>

doi.org/10.1016/j.parkreldis.2021.06.023, hdl.handle.net/1765/135764
Parkinsonism and Related Disorders
Erasmus MC: University Medical Center Rotterdam

A. (Christina) Fevga, Yangshin Park, Ebba Lohmann, J.A. (Anneke) Kievit, G.J. (Guido) Breedveld, F. (Federico) Ferraro, … V. (Vincenzo) Bonifati. (2021). A new alpha-synuclein missense variant (Thr72Met) in two Turkish families with Parkinson's disease. Parkinsonism and Related Disorders, 89, 63–72. doi:10.1016/j.parkreldis.2021.06.023