Hypomorphic mutations in POLR_{3}A$ are a frequent cause of sporadic and recessive spastic ataxia

Autor: Ina Schmitt, Oliver Brüstle, Rajech Sharkia, Kristina Rehbach, Stefan Herms, Jennifer Reichbauer, Feifei Tao, Peter De Jonghe, Susanne Greschus, Garth A. Nicholson, Alfredo Ramirez, Stefanie Heilmann-Heimbach, Ludger Schöls, Michael E. Shy, Thomas Klockgether, Paolo Carloni, Holger Wagner, Dagmar Timmann, Claudia Stendel, Delia Kurzwelly, Marina L. Kennerson, Matthis Synofzik, Patrick F. Chinnery, Wolfgang Maier, Stephan Züchner, Peter Bauer, Angela Pyle, Tim W. Rattay, Michael Peitz, Katrin Amunts, Burcu Atasu, Rüdiger Stirnberg, Holger Hengel, Jonathan Baets, Shawna M. E. Feely, Jürgen Kohlhase, Holger Thiele, M. Lennarz, Janine Altmüller, Ilker Karaca, Katherine D. Mathews, Muhammad Mahanjah, Tobias Lindig, Johanna Jung, Alejandro Giorgetti, Rebecca Schüle, Ebba Lohmann, Marc Sturm, Michael Wolf, Rita Horvath, Thomas Klopstock, Michael A. Gonzalez, Martina Minnerop, Peter Nürnberg, Anne S. Soehn, Sandra Roeske
Jazyk: angličtina
Rok vydání: 2017
Předmět:
0301 basic medicine
Gerontology
Male
leukodystrophy
POLR3A
cerebellar ataxia
hereditary spastic paraplegia
spastic ataxia
Medizin
Cell Culture Techniques
genetics [Introns]
physiopathology [Spinocerebellar Ataxias]
POLR3A protein
human

genetics [Muscle Spasticity]
Compound heterozygosity
genetics [Optic Atrophy]
0302 clinical medicine
diagnostic imaging [Intellectual Disability]
Spastic
genetics [Spinocerebellar Ataxias]
Exome sequencing
Genetics
diagnostic imaging [Spastic Paraplegia
Hereditary]

genetics [Exons]
Middle Aged
Pedigree
Phenotype
Female
medicine.symptom
physiopathology [Optic Atrophy]
Ataxia
diagnostic imaging [Optic Atrophy]
diagnostic imaging [Spinocerebellar Ataxias]
Hereditary spastic paraplegia
physiopathology [Intellectual Disability]
Induced Pluripotent Stem Cells
Neurogenetics
Biology
03 medical and health sciences
genetics [Spastic Paraplegia
Hereditary]

physiopathology [Spastic Paraplegia
Hereditary]

medicine
Humans
genetics [RNA Polymerase III]
ddc:610
Genetic Association Studies
Aged
Cerebellar ataxia
physiopathology [Muscle Spasticity]
Leukodystrophy
diagnostic imaging [Muscle Spasticity]
RNA Polymerase III
modeling
Original Articles
medicine.disease
030104 developmental biology
Mutation
Neurology (clinical)
Human medicine
genetics [Intellectual Disability]
030217 neurology & neurosurgery
Zdroj: Brain
Brain 140(6), 1561-1578 (2017). doi:10.1093/brain/awx095
ISSN: 0006-8950
Popis: 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.
Databáze: OpenAIRE