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- 조회803
Ann. Neurol., First published: 31 March 2018 | https://doi.org/10.1002/ana.25220
Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects
Eunju Seong1, PhD, Ryan Insolera2, PhD, Marija Dulovic3, PhD, Erik-Jan Kamsteeg4, PhD, Joanne Trinh3, PhD, Norbert Bruggemann5, MD, Erin Sandford1, PhD, Sheng Li13, PhD, Ayse Bilge Ozel6, PhD, Jun Z. Li6,7 , PhD, Tamison Jewett8, MD, Anneke J.A. Kievit9, MD PhD, Alexander Munchau3, MD, Vikram Shakkottai10, MD PhD, Christine Klein3, MD, Catherine Collins2, PhD, Katja Lohmann3*, PhD, Bart P. van de Warrenburg11*, MD PhD, Margit Burmeister1,6,7,12*, PhD
1Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA.
1Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA.
2Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
3Institute of Neurogenetics, University of Lubeck, Germany
4Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands
5Department of Neurology, University of Lubeck, Germany
6Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
7Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
8Department of Pediatrics, Section on Medical Genetics, Wake Forest School of Medicine, WinstonSalem, North Carolina, USA.
9Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands
10Departments of Neurology and of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA
11Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
11Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
12Department of Psychiatry, University of Michigan, Ann Arbor, MI 48109, USA.
13Present Address: Bio-X Center, Shanghai Jiao Tong University, China.
*Corresponding authors
*Corresponding authors
Abstract
Objective: To identify novel causes of recessive ataxias, including spinocerebellar ataxia with saccadic intrusions, spastic ataxias and spastic paraplegia.
Methods: In an international collaboration, we independently performed exome sequencing in seven families with recessive ataxia and/or spastic paraplegia. To evaluate the role of VPS13D mutations, we evaluated a Drosophila knock-out model and investigated mitochondrial function in patient-derived fibroblast cultures.
Results: Exome sequencing identified compound heterozygous mutations in VPS13D on chromosome 1p36 in all seven families. This included a large family with 5 affected siblings with spinocerebellar ataxia with saccadic intrusions (SCASI), or spinocerebellar ataxia, recessive, type 4, SCAR4. Linkage to chromosome 1p36 was found in this family with a LOD score of 3.1. The phenotypic spectrum in our 12 patients was broad. Although most presented with ataxia, additional or predominant spasticity was present in 5 patients. Disease onset ranged from infancy to 39 years, and symptoms were slowly progressive and included loss of independent ambulation in 5. All but two patients carried a loss-of-function (nonsense or splice site) mutation on one and a missense mutation on the other allele. Knock-down or removal of Vps13D in Drosophila neurons led to changes in mitochondrial morphology and impairment in mitochondrial distribution along axons. Patient fibroblasts showed altered morphology and functionality including reduced energy production.
Interpretation: Our study demonstrates that compound heterozygous mutations in VPS13D cause movement disorders along the ataxia-spasticity spectrum, making VPS13D the fourth VPS13 paralog involved in neurological disorders. This article is protected by copyright. All rights reserved.
논문정보
- Research article
- 2018년 03월 (BRIC 등록일 2018-04-24)
- 국외 연구진
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