DCTN1 p.K56R in progressive supranuclear palsy. (July 2016)

• Record Type: Journal Article
• Authors: Gustavsson, Emil K.; Trinh, Joanne; Guella, Ilaria; Szu-Tu, Chelsea; Khinda, Jaskaran; Lin, Chin-Hsien; Wu, Ruey-Meei; Stoessl, Jon; Appel-Cresswell, Silke; McKeown, Martin; Rajput, Alex; Rajput, Ali H.; Petersen, Maria Skaalum; Jeon, Beom S.; Aasly, Jan O.; Farrer, Matthew J.
• Is Part Of: Parkinsonism & related disorders. Volume 28(2016)
• Page Start: 56
• Page End: 61
• Publication Date: 2016-07
• Subjects: DCTN1 -- p150Glued -- Progressive supranuclear palsy -- Microtubule -- Mutation -- Parkinsonism; Parkinson's disease -- Periodicals; Movement disorders -- Periodicals; Movement Disorders -- Periodicals; Nerve Degeneration -- Periodicals; Nervous System Diseases -- Periodicals; Parkinson Disease -- Periodicals; Tremor -- Periodicals; Parkinson, Maladie de -- Périodiques; Parkinson's disease; 616.833
• DOI: 10.1016/j.parkreldis.2016.04.025
• Languages: English
• ISSNs: 1353-8020

Abstract

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 < 0.01) were subsequently genotyped in Caucasian (1360 cases and 1009 controls) and Asian cohorts (1046 cases and 830 controls), and the functional implications of pathogenic variants were assessed. 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 nol -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. Highlights: We sequenced DCTN1 (p150 Glued ) in patients with Parkinson's disease, Parkinson-plus syndromes and healthy controls. We found a variant ( DCTN1 p.K56R) in the CAP-Gly domain in two patients with clinical Progressive supranuclear palsy. The variant alters the affinity of p150 Glued for microtubules and causes a more diffuse cytoplasmic protein distribution. The observed clinical phenotype, in p.K56R carriers, expands the phenotypes associated with DCTN1 variants.