DCTN1 p.K56R in progressive supranuclear palsy

Abstract Introduction Mutations in dynactin DCTN1 (p150 glued ) have previously been linked to familial motor neuron disease or Perry syndrome (PS) consisting of depression, parkinsonism and hypoventilation. Methods We sequenced DCTN1 in 636 Caucasian patients with parkinsonism (Parkinson's disease and Parkinson-plus syndromes) and 508 healthy controls. Variants (MAF  Results We identified 17 rare variants leading to non-synonymous amino-acid substitutions. Four of the variants were only observed in control subjects, four in both cases and controls and the remaining nine in cases only. One of the variants, DCTN1 p.K56R, was present in two patients with progressive supranuclear palsy (PSP) with a shared minimal 2.2 Mb haplotype. Both subjects have parkinsonism as the most prominent symptom with abnormal ocular movements, moderate cognitive impairment and little to no l -dopa response. Neither subject presents with depression, central hypoventilation or weight loss. For one of the subjects MRI shows symmetrical atrophy of temporal and frontoparietal lobes. In HEK293 cells mutant p150 glued (p.K56R) shows less affinity for microtubules than wild-type, with a more diffuse cytoplasmic distribution. Conclusions We have identified DCTN1 p.K56R in patients with PSP. This variant is immediately adjacent to the N-terminal p150 glued ‘CAP-Gly’ domain, affects a highly conserved amino acid and alters the protein's affinity to microtubules and its cytoplasmic distribution.