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

Martina Minnerop; Delia Kurzwelly; Holger Wagner; Anne S Soehn; Jennifer Reichbauer; Feifei Tao; Tim W Rattay; Michael Peitz; Kristina Rehbach; Alejandro Giorgetti; Angela Pyle; Holger Thiele; Janine Altmüller; Dagmar Timmann; Ilker Karaca; Martina Lennarz; Jonathan Baets; Holger Hengel; Matthis Synofzik; Burcu Atasu; Shawna Feely; Marina Kennerson; Claudia Stendel; Tobias Lindig; Michael A Gonzalez; Rüdiger Stirnberg; Marc Sturm; Sandra Roeske; Johanna Jung; Peter Bauer; Ebba Lohmann; Stefan Herms; Stefanie Heilmann-Heimbach; Garth Nicholson; Muhammad Mahanjah; Rajech Sharkia; Paolo Carloni; Oliver Brüstle; Thomas Klopstock; Katherine D Mathews; Michael E Shy; Peter de Jonghe; Patrick F Chinnery; Rita Horvath; Jürgen Kohlhase; Ina Schmitt; Michael Wolf; Susanne Greschus; Katrin Amunts; Wolfgang Maier; Ludger Schöls; Peter Nürnberg; Stephan Zuchner; Thomas Klockgether; Alfredo Ramirez; Rebecca Schüle

doi:10.1093/brain/awx095

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

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

Martina Minnerop, Delia Kurzwelly, Holger Wagner, Anne S Soehn, Jennifer Reichbauer, Feifei Tao, Tim W Rattay, Michael Peitz, Kristina Rehbach, Alejandro Giorgetti, …

Brain (London, England : 1878), Vol.140(6), pp.1561-1578

2017-06-01

DOI: https://doi.org/10.1093/brain/awx095

PMCID: PMC6402316

PMID: 28459997

Abstract

Spastic Paraplegia, Hereditary - genetics

Humans

Middle Aged

Male

Intellectual Disability - genetics

Spastic Paraplegia, Hereditary - diagnostic imaging

RNA Polymerase III - genetics

Female

Cell Culture Techniques

Spastic Paraplegia, Hereditary - physiopathology

Optic Atrophy - genetics

Spinocerebellar Ataxias - genetics

Introns - genetics

Genetic Association Studies

Intellectual Disability - diagnostic imaging

Spinocerebellar Ataxias - diagnostic imaging

Optic Atrophy - physiopathology

Exons - genetics

Spinocerebellar Ataxias - physiopathology

Intellectual Disability - physiopathology

Phenotype

Pedigree

Aged

Muscle Spasticity - physiopathology

Muscle Spasticity - diagnostic imaging

Mutation

Induced Pluripotent Stem Cells

Muscle Spasticity - genetics

Optic Atrophy - diagnostic imaging

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.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.203 Neuromuscular Disorders; 1.203.1430 Oligodendrocyte
Web Of Science research areas: Clinical Neurology; Neurosciences
ESI research areas: Neuroscience & Behavior

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Title: 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, Germany
Delia Kurzwelly - German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany
Holger Wagner - Department of Psychiatry and Psychotherapy, University of Bonn, 53127 Bonn, Germany
Anne S Soehn - Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany
Jennifer Reichbauer - German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany
Feifei 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, USA
Tim W Rattay - German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany
Michael Peitz - Institute of Reconstructive Neurobiology, Life and Brain Center, 53127 Bonn, Germany
Kristina Rehbach - Institute of Reconstructive Neurobiology, Life and Brain Center, 53127 Bonn, Germany
Alejandro Giorgetti - Department of Biotechnology, University of Verona, 37134 Verona, Italy
Angela Pyle - Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK
Holger Thiele - Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany
Janine Altmüller - Institute of Human Genetics, University Hospital of Cologne, 50931 Cologne, Germany
Dagmar Timmann - Department of Neurology, University of Duisburg-Essen, 45147 Essen, Germany
Ilker Karaca - Department of Psychiatry and Psychotherapy, University of Bonn, 53127 Bonn, Germany
Martina Lennarz - Department of Psychiatry and Psychotherapy, University of Bonn, 53127 Bonn, Germany
Jonathan Baets - Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium
Holger Hengel - German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany
Matthis Synofzik - German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany
Burcu Atasu - Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany
Shawna Feely - Department of Neurology, University of Iowa, 52242 Iowa, USA
Marina Kennerson - Sydney Medical School, University of Sydney, Sydney NSW 2006, Australia
Claudia Stendel - German Center for Neurodegenerative Diseases (DZNE), 81337 Munich, Germany
Tobias Lindig - Department of Diagnostic and Interventional Neuroradiology, University Hospital Tübingen, 72076 Tübingen, Germany
Michael 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, USA
Rüdiger Stirnberg - German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany
Marc Sturm - Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany
Sandra Roeske - German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany
Johanna Jung - German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany
Peter Bauer - Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany
Ebba Lohmann - Behavioural Neurology and Movement Disorders Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 34093 Istanbul, Turkey
Stefan Herms - Division of Medical Genetics, University Hospital and Department of Biomedicine, University of Basel, CH-4058, Basel, Switzerland
Stefanie Heilmann-Heimbach - Department of Genomics, Life and Brain Center, University of Bonn, 53127, Bonn, Germany
Garth Nicholson - Sydney Medical School, University of Sydney, Sydney NSW 2006, Australia
Muhammad Mahanjah - Bruce and Ruth Rappaport Faculty of Medicine, Technion, 31096 Haifa, Israel
Rajech Sharkia - Beit-Berl Academic College, Beit-Berl 44905, Israel
Paolo 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, Germany
Oliver Brüstle - Institute of Reconstructive Neurobiology, Life and Brain Center, 53127 Bonn, Germany
Thomas Klopstock - Munich Cluster of Systems Neurology (SyNergy), 80336 Munich, Germany
Katherine D Mathews - Department of Pediatrics, Carver College of Medicine, University of Iowa, 52242 Iowa, USA
Michael E Shy - Department of Neurology, University of Iowa, 52242 Iowa, USA
Peter de Jonghe - Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium
Patrick F Chinnery - Department of Clinical Neurosciences, Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 0QQ, UK
Rita Horvath - Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK
Jürgen Kohlhase - Center for Human Genetics Freiburg, 79100 Freiburg, Germany
Ina Schmitt - Department of Neurology, University of Bonn, 53127 Bonn, Germany
Michael Wolf - Departement of Orthodontics, University of Bonn, 53111 Bonn, Germany
Susanne Greschus - Department of Radiology, University of Bonn, 53127 Bonn, Germany
Katrin Amunts - C. & O. Vogt-Institute of Brain Research, University of Düsseldorf, 40212 Düsseldorf, Germany
Wolfgang Maier - Department of Psychiatry and Psychotherapy, University of Bonn, 53127 Bonn, Germany
Ludger Schöls - German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany
Peter Nürnberg - Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
Stephan 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, USA
Thomas Klockgether - German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany
Alfredo Ramirez - Department of Psychiatry and Psychotherapy, University of Cologne, 50937 Cologne, Germany
Rebecca 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
Publication Details: Brain (London, England : 1878), Vol.140(6), pp.1561-1578
Publisher: England
Grant note: MC_UP_1501/2 / Medical Research Council MR/N025431/1 / Medical Research Council R01 NS072248 / NINDS NIH HHS
Academic Unit: Leadership Department; Miller School of Medicine; John P. Hussman Institute for Human Genomics
Language: English
Resource Type: Journal article
PMID: 28459997
PMCID: PMC6402316
Record Identifier: 991031576495302976