Loss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities.
Journal
Annals of neurology
ISSN: 1531-8249
Titre abrégé: Ann Neurol
Pays: United States
ID NLM: 7707449
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
12
05
2020
revised:
31
07
2020
accepted:
09
08
2020
pubmed:
19
8
2020
medline:
15
12
2020
entrez:
19
8
2020
Statut:
ppublish
Résumé
The majority of people with suspected genetic dystonia remain undiagnosed after maximal investigation, implying that a number of causative genes have not yet been recognized. We aimed to investigate this paucity of diagnoses. We undertook weighted burden analysis of whole-exome sequencing (WES) data from 138 individuals with unresolved generalized dystonia of suspected genetic etiology, followed by additional case-finding from international databases, first for the gene implicated by the burden analysis (VPS16), and then for other functionally related genes. Electron microscopy was performed on patient-derived cells. Analysis revealed a significant burden for VPS16 (Fisher's exact test p value, 6.9 × 10 Our study strongly supports a role for HOPS complex dysfunction in the pathogenesis of dystonia, although variants in different subunits display different phenotypic and inheritance characteristics. ANN NEUROL 2020;88:867-877.
Substances chimiques
VPS16 protein, human
0
VPS41 protein, human
0
Vesicular Transport Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
867-877Subventions
Organisme : Department of Health
ID : RP-2016-07-019
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P008593/1
Pays : United Kingdom
Organisme : Cancer Research UK
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S006753/1
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Type : CommentIn
Informations de copyright
© 2020 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
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