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Brain. 2017 Jun 1;140(6):1561-1578. doi: 10.1093/brain/awx095.

Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia.

Author information

1
Institute of Neuroscience and Medicine (INM-1), Research Centre Juelich, 52425 Jülich, Germany.
2
Department of Neurology, University of Bonn, 53127 Bonn, Germany.
3
German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany.
4
Department of Psychiatry and Psychotherapy, University of Bonn, 53127 Bonn, Germany.
5
Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany.
6
Center for Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.
7
German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany.
8
Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
9
Institute of Reconstructive Neurobiology, Life and Brain Center, 53127 Bonn, Germany.
10
Computational Biophysics, German Research School for Simulation Sciences, and Computational Biomedicine, Institute for Advanced Simulation (IAS-5) and Institute of Neuroscience and Medicine (INM-9), Research Centre Juelich, 52425 Jülich, Germany.
11
Department of Biotechnology, University of Verona, 37134 Verona, Italy.
12
Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
13
Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany.
14
Institute of Human Genetics, University Hospital of Cologne, 50931 Cologne, Germany.
15
Department of Neurology, University of Duisburg-Essen, 45147 Essen, Germany.
16
Neurogenetics Group, VIB-Department of Molecular Genetics, VIB, 2610 Antwerp, Belgium.
17
Department of Neurology, Antwerp University Hospital, 2650 Antwerp, Belgium.
18
Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium.
19
Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.
20
Department of Neurology, University of Iowa, 52242 Iowa, USA.
21
Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord NSW 2139, Australia.
22
Molecular Medicine Laboratory, Concord Hospital, Concord NSW 2139, Australia.
23
Sydney Medical School, University of Sydney, Sydney NSW 2006, Australia.
24
Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-Universität, 80336 Munich, Germany.
25
German Center for Neurodegenerative Diseases (DZNE), 81337 Munich, Germany.
26
Department of Diagnostic and Interventional Neuroradiology, University Hospital Tübingen, 72076 Tübingen, Germany.
27
Behavioural Neurology and Movement Disorders Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 34093 Istanbul, Turkey.
28
Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
29
Department of Genomics, Life and Brain Center, University of Bonn, 53127, Bonn, Germany.
30
Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, CH-4058, Basel, Switzerland.
31
Child Neurology and Development Center, Hillel-Yaffe Medical Center, 38100 Hadera, Israel.
32
Bruce and Ruth Rappaport Faculty of Medicine, Technion, 31096 Haifa, Israel.
33
The Triangle Regional Research and Development Center, P. O. Box-2167, Kfar Qari' 30075, Israel.
34
Beit-Berl Academic College, Beit-Berl 44905, Israel.
35
Munich Cluster of Systems Neurology (SyNergy), 80336 Munich, Germany.
36
Department of Pediatrics, Carver College of Medicine, University of Iowa, 52242 Iowa, USA.
37
Department of Clinical Neurosciences, Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 0QQ, UK.
38
Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
39
Center for Human Genetics Freiburg, 79100 Freiburg, Germany.
40
Departement of Orthodontics, University of Bonn, 53111 Bonn, Germany.
41
Department of Radiology, University of Bonn, 53127 Bonn, Germany.
42
C. & O. Vogt-Institute of Brain Research, University of Düsseldorf, 40212 Düsseldorf, Germany.
43
Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany.
44
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
45
Department of Psychiatry and Psychotherapy, University of Cologne, 50937 Cologne, Germany.

Erratum in

Abstract

Despite extensive efforts, half of patients with rare movement disorders such as hereditary spastic paraplegias and cerebellar ataxias remain genetically unexplained, implicating novel genes and unrecognized mutations in known genes. Non-coding DNA variants are suspected to account for a substantial part of undiscovered causes of rare diseases. Here we identified mutations located deep in introns of POLR3A to be a frequent cause of hereditary spastic paraplegia and cerebellar ataxia. First, whole-exome sequencing findings in a recessive spastic ataxia family turned our attention to intronic variants in POLR3A, a gene previously associated with hypomyelinating leukodystrophy type 7. Next, we screened a cohort of hereditary spastic paraplegia and cerebellar ataxia cases (n = 618) for mutations in POLR3A and identified compound heterozygous POLR3A mutations in ∼3.1% of index cases. Interestingly, >80% of POLR3A mutation carriers presented the same deep-intronic mutation (c.1909+22G>A), which activates a cryptic splice site in a tissue and stage of development-specific manner and leads to a novel distinct and uniform phenotype. The phenotype is characterized by adolescent-onset progressive spastic ataxia with frequent occurrence of tremor, involvement of the central sensory tracts and dental problems (hypodontia, early onset of severe and aggressive periodontal disease). Instead of the typical hypomyelination magnetic resonance imaging pattern associated with classical POLR3A mutations, cases carrying c.1909+22G>A demonstrated hyperintensities along the superior cerebellar peduncles. These hyperintensities may represent the structural correlate to the cerebellar symptoms observed in these patients. The associated c.1909+22G>A variant was significantly enriched in 1139 cases with spastic ataxia-related phenotypes as compared to unrelated neurological and non-neurological phenotypes and healthy controls (P = 1.3 × 10-4). In this study we demonstrate that (i) autosomal-recessive mutations in POLR3A are a frequent cause of hereditary spastic ataxias, accounting for about 3% of hitherto genetically unclassified autosomal recessive and sporadic cases; and (ii) hypomyelination is frequently absent in POLR3A-related syndromes, especially when intronic mutations are present, and thus can no longer be considered as the unifying feature of POLR3A disease. Furthermore, our results demonstrate that substantial progress in revealing the causes of Mendelian diseases can be made by exploring the non-coding sequences of the human genome.

KEYWORDS:

POLR3A; cerebellar ataxia; hereditary spastic paraplegia; leukodystrophy; spastic ataxia

PMID:
28459997
PMCID:
PMC6402316
DOI:
10.1093/brain/awx095
[Indexed for MEDLINE]
Free PMC Article

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