DCTN1 p.K56R in progressive supranuclear palsy
Journal
Parkinsonism and Related Disorders
Journal Volume
28
Pages
56-61
Date Issued
2016
Author(s)
Gustavsson E.K.
Trinh J.
Guella I.
Szu-Tu C.
Khinda J.
Stoessl J.
Appel-Cresswell S.
McKeown M.
Rajput A.
Rajput A.H.
Petersen M.S.
Jeon B.S.
Aasly J.O.
Farrer M.J.
Abstract
Introduction: Mutations in dynactin DCTN1 (p150glued) 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 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 p150glued (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 p150glued 'CAP-Gly' domain, affects a highly conserved amino acid and alters the protein's affinity to microtubules and its cytoplasmic distribution. ? 2016 Elsevier Ltd.
SDGs
Other Subjects
levodopa; WT1 protein; DCTN1 protein, human; dynactin; adolescent; adult; aged; Article; Beck Depression Inventory; cellular distribution; child; controlled study; corticobasal degeneration; DCTN1 gene; diffuse Lewy body disease; disease course; ethnicity; female; gene; gene mutation; gene sequence; genetic screening; genetic variability; haplotype; human; human cell; major clinical study; male; Mini Mental State Examination; Montreal cognitive assessment; onset age; Parkinson disease; priority journal; progressive supranuclear palsy; protein localization; Shy Drager syndrome; genetics; HEK293 cell line; middle aged; mutation; Parkinson disease; parkinsonism; pathophysiology; phenotype; progressive supranuclear palsy; very elderly; young adult; Adult; Aged; Aged, 80 and over; Dynactin Complex; Female; HEK293 Cells; Humans; Male; Middle Aged; Mutation; Parkinson Disease; Parkinsonian Disorders; Phenotype; Supranuclear Palsy, Progressive; Young Adult
Type
journal article