Alpha‐synuclein p.H50Q, a novel pathogenic mutation for Parkinson's disease

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Alpha-synuclein plays a central role in the pathophysiology of Parkinson's disease. Three missense mutations in SNCA, the gene encoding alpha-synuclein, as well as genomic multiplications have been identified as causes for autosomal-dominantly inherited Parkinsonism. Here, we describe a novel missense mutation in exon 4 of SNCA encoding a H50Q substitution in a patient with dopa-responsive Parkinson's disease with a family history of parkinsonism and dementia. The variant was not observed in public databases or identified in unrelated subjects. The substitution's evolutionary conservation and protein modeling provide additional support for pathogenicity as the amino acid perturbs the same amphipathic alpha helical structure as the previously described pathogenic mutations.