Journal article
Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia
Brain (London, England : 1878), Vol.140(6), pp.1561-1578
06/01/2017
DOI: 10.1093/brain/awx095
PMCID: PMC6402316
PMID: 28459997
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.
Details
- Title: Subtitle
- Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia
- Creators
- Martina Minnerop - Department of Neurology, University of Bonn, 53127 Bonn, GermanyDelia Kurzwelly - German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, GermanyHolger Wagner - Department of Psychiatry and Psychotherapy, University of Bonn, 53127 Bonn, GermanyAnne S Soehn - Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, GermanyJennifer Reichbauer - German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, GermanyFeifei Tao - 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, USATim W Rattay - German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, GermanyMichael Peitz - Institute of Reconstructive Neurobiology, Life and Brain Center, 53127 Bonn, GermanyKristina Rehbach - Institute of Reconstructive Neurobiology, Life and Brain Center, 53127 Bonn, GermanyAlejandro Giorgetti - Department of Biotechnology, University of Verona, 37134 Verona, ItalyAngela Pyle - Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UKHolger Thiele - Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, GermanyJanine Altmüller - Institute of Human Genetics, University Hospital of Cologne, 50931 Cologne, GermanyDagmar Timmann - Department of Neurology, University of Duisburg-Essen, 45147 Essen, GermanyIlker Karaca - Department of Psychiatry and Psychotherapy, University of Bonn, 53127 Bonn, GermanyMartina Lennarz - Department of Psychiatry and Psychotherapy, University of Bonn, 53127 Bonn, GermanyJonathan Baets - Institute Born-Bunge, University of Antwerp, 2610 Antwerp, BelgiumHolger Hengel - German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, GermanyMatthis Synofzik - German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, GermanyBurcu Atasu - Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, GermanyShawna Feely - Department of Neurology, University of Iowa, 52242 Iowa, USAMarina Kennerson - Sydney Medical School, University of Sydney, Sydney NSW 2006, AustraliaClaudia Stendel - German Center for Neurodegenerative Diseases (DZNE), 81337 Munich, GermanyTobias Lindig - Department of Diagnostic and Interventional Neuroradiology, University Hospital Tübingen, 72076 Tübingen, GermanyMichael A Gonzalez - 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, USARüdiger Stirnberg - German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, GermanyMarc Sturm - Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, GermanySandra Roeske - German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, GermanyJohanna Jung - German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, GermanyPeter Bauer - Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, GermanyEbba Lohmann - Behavioural Neurology and Movement Disorders Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 34093 Istanbul, TurkeyStefan Herms - Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, CH-4058, Basel, SwitzerlandStefanie Heilmann-Heimbach - Department of Genomics, Life and Brain Center, University of Bonn, 53127, Bonn, GermanyGarth Nicholson - Sydney Medical School, University of Sydney, Sydney NSW 2006, AustraliaMuhammad Mahanjah - Bruce and Ruth Rappaport Faculty of Medicine, Technion, 31096 Haifa, IsraelRajech Sharkia - Beit-Berl Academic College, Beit-Berl 44905, IsraelPaolo Carloni - 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, GermanyOliver Brüstle - Institute of Reconstructive Neurobiology, Life and Brain Center, 53127 Bonn, GermanyThomas Klopstock - Munich Cluster of Systems Neurology (SyNergy), 80336 Munich, GermanyKatherine D Mathews - Department of Pediatrics, Carver College of Medicine, University of Iowa, 52242 Iowa, USAMichael E Shy - Department of Neurology, University of Iowa, 52242 Iowa, USAPeter de Jonghe - Institute Born-Bunge, University of Antwerp, 2610 Antwerp, BelgiumPatrick F Chinnery - Department of Clinical Neurosciences, Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 0QQ, UKRita Horvath - Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UKJürgen Kohlhase - Center for Human Genetics Freiburg, 79100 Freiburg, GermanyIna Schmitt - Department of Neurology, University of Bonn, 53127 Bonn, GermanyMichael Wolf - Departement of Orthodontics, University of Bonn, 53111 Bonn, GermanySusanne Greschus - Department of Radiology, University of Bonn, 53127 Bonn, GermanyKatrin Amunts - C. & O. Vogt-Institute of Brain Research, University of Düsseldorf, 40212 Düsseldorf, GermanyWolfgang Maier - Department of Psychiatry and Psychotherapy, University of Bonn, 53127 Bonn, GermanyLudger Schöls - German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, GermanyPeter Nürnberg - Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, GermanyStephan Zuchner - 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, USAThomas Klockgether - German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, GermanyAlfredo Ramirez - Department of Psychiatry and Psychotherapy, University of Cologne, 50937 Cologne, GermanyRebecca Schüle - 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
- Resource Type
- Journal article
- Publication Details
- Brain (London, England : 1878), Vol.140(6), pp.1561-1578
- Publisher
- England
- DOI
- 10.1093/brain/awx095
- PMID
- 28459997
- PMCID
- PMC6402316
- ISSN
- 0006-8950
- eISSN
- 1460-2156
- Grant note
- MC_UP_1501/2 / Medical Research Council MR/N025431/1 / Medical Research Council R01 NS072248 / NINDS NIH HHS
- Language
- English
- Date published
- 06/01/2017
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics)
- Record Identifier
- 9984070809502771
Metrics
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