@article{journal article,
	author = {Steel, Dora and Zech, Michael and Zhao, Chen and Barwick, Katy E S and Burke, Derek and Demailly, Diane and Kumar, Kishore R and Zorzi, Giovanna and Nardocci, Nardo and Kaiyrzhanov, Rauan and Wagner, Matias and Iuso, Arcangela and Berutti, Riccardo and Škorvánek, Matej and Necpál, Ján and Davis, Ryan and Wiethoff, Sarah and Mankad, Kshitij and Sudhakar, Sniya and Ferrini, Arianna and Sharma, Suvasini and Kamsteeg, Erik-Jan and Tijssen, Marina A and Verschuuren, Corien and van Egmond, Martje E and Flowers, Joanna M and McEntagart, Meriel and Tucci, Arianna and Coubes, Philippe and Bustos, Bernabe I and Gonzalez-Latapi, Paulina and Tisch, Stephen and Darveniza, Paul and Gorman, Kathleen M and Peall, Kathryn J and Bötzel, Kai and Koch, Jan C and Kmieć, Tomasz and Plecko, Barbara and Boesch, Sylvia and Haslinger, Bernhard and Jech, Robert and Garavaglia, Barbara and Wood, Nick and Houlden, Henry and Gissen, Paul and Lubbe, Steven J and Sue, Carolyn M and Cif, Laura and Mencacci, Niccolò E and Anderson, Glenn and Kurian, Manju A and Winkelmann, Juliane},
	title = {Loss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities.},

	year = {2020},

        volume = {88},


        number = {5},

        pages = {867-877},

        issn = {0364-5134},

        doi = {10.1002/ana.25879},


        abstract = {OBJECTIVES: 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.
METHODS: 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.
RESULTS: 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.
INTERPRETATION: 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.
},


	
}