Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Steel, D; Zech, M; Zhao, C; Barwick, KES; Burke, D; Demailly, D; Kumar, KR; Zorzi, G; Nardocci, N; Kaiyrzhanov, R; Wagner, M; Iuso, A; Berutti, R; Škorvánek, M; Necpál, J; Davis, R; Wiethoff, S; Mankad, K; Sudhakar, S; Ferrini, A; Sharma, S; Kamsteeg, EJ; Tijssen, MA; Verschuuren, C; van Egmond, ME; Flowers, JM; McEntagart, M; Tucci, A; Coubes, P; Bustos, BI; Gonzalez-Latapi, P; Tisch, S; Darveniza, P; Gorman, KM; Peall, KJ; Bötzel, K; Koch, JC; Kmieć, T; Plecko, B; Boesch, S; Haslinger, B; Jech, R; Garavaglia, B; Wood, N; Houlden, H; Gissen, P; Lubbe, SJ; Sue, CM; Cif, L; Mencacci, NE; Anderson, G; Kurian, MA; Winkelmann, J; Genomics England Research Consortium.
Loss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities.
Ann Neurol. 2020; 88(5):867-877
Doi: 10.1002/ana.25879
[OPEN ACCESS]
Web of Science
PubMed
FullText
FullText_MUG
- Co-Autor*innen der Med Uni Graz
- Plecko Barbara
- Altmetrics:
- Dimensions Citations:
- Plum Analytics:
- Scite (citation analytics):
- Abstract:
- 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 × 109 ). VPS16 encodes a subunit of the homotypic fusion and vacuole protein sorting (HOPS) complex, which plays a key role in autophagosome-lysosome fusion. A total of 18 individuals harboring heterozygous loss-of-function VPS16 variants, and one with a microdeletion, were identified. These individuals experienced early onset progressive dystonia with predominant cervical, bulbar, orofacial, and upper limb involvement. Some patients had a more complex phenotype with additional neuropsychiatric and/or developmental comorbidities. We also identified biallelic loss-of-function variants in VPS41, another HOPS-complex encoding gene, in an individual with infantile-onset generalized dystonia. Electron microscopy of patient-derived lymphocytes and fibroblasts from both patients with VPS16 and VPS41 showed vacuolar abnormalities suggestive of impaired lysosomal function. 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. © 2020 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
- Find related publications in this database (using NLM MeSH Indexing)
- Adult -
- Cost of Illness -
- Dystonia - genetics
- Dystonia - pathology
- Exome - genetics
- Female -
- Fibroblasts - pathology
- Genetic Predisposition to Disease - genetics
- Genetic Variation -
- Humans -
- Lysosomal Storage Diseases - genetics
- Lysosomal Storage Diseases - pathology
- Male -
- Middle Aged -
- Mutation - genetics
- Pedigree -
- Vesicular Transport Proteins - genetics