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

TLDR

Alpha‑synuclein is central to Parkinson's disease pathophysiology, and three missense mutations in SNCA plus genomic multiplications have been identified as causes of autosomal‑dominant Parkinsonism. The study reports a novel H50Q missense mutation in exon 4 of SNCA in a dopa‑responsive Parkinson's disease patient with a family history of parkinsonism and dementia. The H50Q variant was absent from public databases and unrelated subjects, and evolutionary conservation plus protein modeling indicate it disrupts the amphipathic alpha‑helical structure, supporting pathogenicity. © 2013 Movement Disorder Society.

Abstract

ABSTRACT Background 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. Methods 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. Results The variant was not observed in public databases or identified in unrelated subjects. Conclusions 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. © 2013 Movement Disorder Society