DCTN1 p.K56R in progressive supranuclear palsy

Emil K. Gustavsson; Joanne Trinh; Ilaria Guella; Chelsea Szu-Tu; Jaskaran Khinda; Chin Hsien Lin; Ruey Meei Wu; A. Jon Stoessl; Silke Appel-Cresswell; Martin McKeown; Alex Rajput; Ali H. Rajput; Maria Skaalum Petersen; Beom S. Jeon; Jan O. Aasly; Matthew Farrer

doi:10.1016/j.parkreldis.2016.04.025

DCTN1 p.K56R in progressive supranuclear palsy

Emil K. Gustavsson, Joanne Trinh, Ilaria Guella, Chelsea Szu-Tu, Jaskaran Khinda, Chin Hsien Lin, Ruey Meei Wu, A. Jon Stoessl, Silke Appel-Cresswell, Martin McKeown, Alex Rajput, Ali H. Rajput, Maria Skaalum Petersen, Beom S. Jeon, Jan O. Aasly, Matthew Farrer

Institute of Neurogenetics

33 Citations (Scopus)

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 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.

Original language	English
Journal	Parkinsonism and Related Disorders
Volume	28
Pages (from-to)	56-61
Number of pages	6
ISSN	1353-8020
DOIs	https://doi.org/10.1016/j.parkreldis.2016.04.025
Publication status	Published - 01.07.2016

Funding

Canada Excellence Research Chairs program (M.J.F.), Canada Research Chairs (A.J.S.), The Peter Cundill Foundation (A.J.S & M.J.F), Leading Edge Endowment Funds provided by the Province of British Columbia, LifeLabs, and Genome BC which support the Dr. Donald Rix BC Leadership Chair (M.J.F), as well as the Pacific Parkinson's Research Institute (S.A.C.), and the Canadian Institutes of Health Research (A.J.S.). Ali H. Rajput - Participated in a clinical trial funded by Teva (TVP-1012/501), was funded by them to attend a meeting and has received honoraria from Allergan. We are grateful to all individuals who generously participated in this study. This research was undertaken, in part, thanks to funding from the Canada Excellence Research Chairs program (MJF) , Leading Edge Endowment Funds provided by the Province of British Columbia , LifeLabs, and Genome BC support the Dr. Donald Rix BC Leadership Chair (MJF), and the Cundhill Foundation (MJF). The Faroese project has been supported by the Faroese Research Council and the Faroese and Danish Parkinson Associations . We appreciate the technical contribution from Daniel M. Evans, Vanessa Silva and Stephanie F Bortnick.

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Gustavsson, E. K., Trinh, J., Guella, I., Szu-Tu, C., Khinda, J., Lin, C. H., Wu, R. M., Stoessl, A. J., Appel-Cresswell, S., McKeown, M., Rajput, A., Rajput, A. H., Petersen, M. S., Jeon, B. S., Aasly, J. O., & Farrer, M. (2016). DCTN1 p.K56R in progressive supranuclear palsy. Parkinsonism and Related Disorders, 28, 56-61. https://doi.org/10.1016/j.parkreldis.2016.04.025

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title = "DCTN1 p.K56R in progressive supranuclear palsy",

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.",

author = "Gustavsson, \{Emil K.\} and Joanne Trinh and Ilaria Guella and Chelsea Szu-Tu and Jaskaran Khinda and Lin, \{Chin Hsien\} and Wu, \{Ruey Meei\} and Stoessl, \{A. Jon\} and Silke Appel-Cresswell and Martin McKeown and Alex Rajput and Rajput, \{Ali H.\} and Petersen, \{Maria Skaalum\} and Jeon, \{Beom S.\} and Aasly, \{Jan O.\} and Matthew Farrer",

note = "Publisher Copyright: {\textcopyright} 2016 Elsevier Ltd.",

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month = jul,

day = "1",

doi = "10.1016/j.parkreldis.2016.04.025",

language = "English",

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pages = "56--61",

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TY - JOUR

T1 - DCTN1 p.K56R in progressive supranuclear palsy

AU - Gustavsson, Emil K.

AU - Trinh, Joanne

AU - Guella, Ilaria

AU - Szu-Tu, Chelsea

AU - Khinda, Jaskaran

AU - Lin, Chin Hsien

AU - Wu, Ruey Meei

AU - Stoessl, A. Jon

AU - Appel-Cresswell, Silke

AU - McKeown, Martin

AU - Rajput, Alex

AU - Rajput, Ali H.

AU - Petersen, Maria Skaalum

AU - Jeon, Beom S.

AU - Aasly, Jan O.

AU - Farrer, Matthew

PY - 2016/7/1

Y1 - 2016/7/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84964600646

U2 - 10.1016/j.parkreldis.2016.04.025

DO - 10.1016/j.parkreldis.2016.04.025

M3 - Journal articles

C2 - 27132499

AN - SCOPUS:84964600646

SN - 1353-8020

VL - 28

SP - 56

EP - 61

JO - Parkinsonism and Related Disorders

JF - Parkinsonism and Related Disorders

ER -

DCTN1 p.K56R in progressive supranuclear palsy

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