Faculty Collaboration Database

Novel destabilizing Dynactin variant (DCTN1 p.Tyr78His) in patient with Perry syndrome. Parkinsonism Relat Disord 2020 Aug;77:110-113

Date

07/28/2020

Pubmed ID

32712562

DOI

10.1016/j.parkreldis.2020.06.006

Scopus ID

2-s2.0-85088215494 (requires institutional sign-in at Scopus site)   6 Citations

Abstract

INTRODUCTION: Perry syndrome, also recognized as Perry disease, is a rare autosomal dominant disorder characterized by midlife-onset atypical parkinsonism, apathy or depression, respiratory failure and weight loss caused by a mutation in the Dynactin (DCTN1) gene.

CASE DESCRIPTION: A fifty-six years-old adopted male presented with atypical parkinsonism with bradykinesia and postural instability, apathy, weight loss, and recurrent respiratory failure due to central hypoventilation requiring tracheostomy.

METHODS AND RESULTS: Clinical workup revealed a novel DCTN1 p.Tyr78His variant. Using bioinformatic protein structure modeling, we compare our patient's variant to known DCTN1 mutations and predict protein stability of each variant at the CAP-Gly domain of p150^Glued. All eight variants causing Perry syndrome, as well as Tyr78His, are located at site expected to interact with MAPRE1 tail and are predicted to be destabilizing. Variants causing atypical parkinsonism with incomplete Perry syndrome phenotype (K56R and K68E) are not significantly destabilizing in silico.

CONCLUSION: We propose p.Tyr78His as the ninth pathogenic DCTN1 variant causing Perry syndrome. Bioinformatic protein modeling may provide additional window to understand and interpret DCTN1 variants, as we observed non-destabilizing variants to have different phenotype than destabilizing variants.

Author List

Čierny M, Hooshmand SI, Fee D, Tripathi S, Dsouza NR, La Pean Kirschner A, Zimmermann MT, Brennan R

Authors

Ryan T. Brennan DO Assistant Professor in the Neurology department at Medical College of Wisconsin
Marek Cierny MD Adjunct Assistant Professor in the Neurology department at Medical College of Wisconsin
Dominic B. Fee MD Vice Chair, Professor in the Neurology department at Medical College of Wisconsin
Sam I. Hooshmand DO Assistant Professor in the Neurology department at Medical College of Wisconsin
Michael T. Zimmermann PhD Director, Assistant Professor in the Clinical and Translational Science Institute department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Depression
Dynactin Complex
Humans
Hypoventilation
Male
Middle Aged
Mutation
Parkinsonian Disorders
Phenotype