Absence of an orphan mitochondrial protein, c19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation |
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Authors: | Hartig Monika B Iuso Arcangela Haack Tobias Kmiec Tomasz Jurkiewicz Elzbieta Heim Katharina Roeber Sigrun Tarabin Victoria Dusi Sabrina Krajewska-Walasek Malgorzata Jozwiak Sergiusz Hempel Maja Winkelmann Juliane Elstner Matthias Oexle Konrad Klopstock Thomas Mueller-Felber Wolfgang Gasser Thomas Trenkwalder Claudia Tiranti Valeria Kretzschmar Hans Schmitz Gerd Strom Tim M Meitinger Thomas Prokisch Holger |
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Institution: | 1Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany;2Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany;3Department of Child Neurology, Memorial Children's Health Institute, 04-730 Warsaw, Poland;4Magnetic Resonance Imaging Unit, Memorial Children's Health Institute, 04-730 Warsaw, Poland;5Center for Neuropathology and Prion Research, Ludwigs Maximilians University, 81377 Munich, Germany;6Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, 93053 Regensburg, Germany;7Unit of Molecular Neurogenetics, Neurological Institute “Carlo Besta” – Istituto Di Ricovero e Cura a Carattere Scientifico Foundation, 20100 Milan, Italy;8Department of Medical Genetics, Memorial Children's Health Institute, 04-730 Warsaw, Poland;9Department of Neurology, Technische Universität München, 81675 Munich, Germany;10Department of Neurology, Ludwig Maximilian University, 81377 Munich, Germany;11Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, 81337 Munich, Germany;12Hertie-Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, and German Center for Neurodegenerative Diseases, 72076 Tübingen, Germany;13University of Göttingen and Paracelsus-Elena Klinik, 34128 Kassel, Germany |
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Abstract: | The disease classification neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of progressive neurodegenerative disorders characterized by brain iron deposits in the basal ganglia. For about half of the cases, the molecular basis is currently unknown. We used homozygosity mapping followed by candidate gene sequencing to identify a homozygous 11 bp deletion in the orphan gene C19orf12. Mutation screening of 23 ideopathic NBIA index cases revealed two mutated alleles in 18 of them, and one loss-of-function mutation is the most prevalent. We also identified compound heterozygous missense mutations in a case initially diagnosed with Parkinson disease at age 49. Psychiatric signs, optic atrophy, and motor axonal neuropathy were common findings. Compared to the most prevalent NBIA subtype, pantothenate kinase associated neurodegeneration (PKAN), individuals with two C19orf12 mutations were older at age of onset and the disease progressed more slowly. A polyclonal antibody against the predicted membrane spanning protein showed a mitochondrial localization. A histopathological examination in a single autopsy case detected Lewy bodies, tangles, spheroids, and tau pathology. The mitochondrial localization together with the immunohistopathological findings suggests a pathomechanistic overlap with common forms of neurodegenerative disorders. |
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