Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I |
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| Authors: | Guelly Christian Zhu Peng-Peng Leonardis Lea Papić Lea Zidar Janez Schabhüttl Maria Strohmaier Heimo Weis Joachim Strom Tim M Baets Jonathan Willems Jan De Jonghe Peter Reilly Mary M Fröhlich Eleonore Hatz Martina Trajanoski Slave Pieber Thomas R Janecke Andreas R Blackstone Craig Auer-Grumbach Michaela |
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| Institution: | 1Center for Medical Research, Medical University of Graz, Graz 8010, Austria;2Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA;3Institute of Clinical Neurophysiology University Clinical Center, Ljubljana 1000, Slovenia;4Department of Internal Medicine, Division of Endocrinology and Metabolism, Medical University Graz, Graz 8036, Austria;5Institute of Neuropathology, Medical Faculty, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen 52074, Germany;6Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, 85764, Germany;7Neurogenetics Group, VIB Department of Molecular Genetics, University of Antwerp 2610, Belgium;8Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp 2610, Belgium;9Division of Neurology, University Hospital Antwerp, Antwerp 2650, Belgium;10Department of Physical and Rehabilitation Medicine, Hospital Network Antwerp Middelheim, Antwerp 2020, Belgium;11Medical Research Centre for Neuromuscular Diseases, University College London Institute of Neurology, London WC1N 3BG, UK;12Department of Pediatrics II and Division of Human Genetics, Innsbruck Medical University, Innsbruck 6020, Austria |
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| Abstract: | Hereditary sensory neuropathy type I (HSN I) is an axonal form of autosomal-dominant hereditary motor and sensory neuropathy distinguished by prominent sensory loss that leads to painless injuries. Unrecognized, these can result in delayed wound healing and osteomyelitis, necessitating distal amputations. To elucidate the genetic basis of an HSN I subtype in a family in which mutations in the few known HSN I genes had been excluded, we employed massive parallel exon sequencing of the 14.3 Mb disease interval on chromosome 14q. We detected a missense mutation (c.1065C>A, p.Asn355Lys) in atlastin-1 (ATL1), a gene that is known to be mutated in early-onset hereditary spastic paraplegia SPG3A and that encodes the large dynamin-related GTPase atlastin-1. The mutant protein exhibited reduced GTPase activity and prominently disrupted ER network morphology when expressed in COS7 cells, strongly supporting pathogenicity. An expanded screen in 115 additional HSN I patients identified two further dominant ATL1 mutations (c.196G>C p.Glu66Gln] and c.976 delG p.Val326TrpfsX8]). This study highlights an unexpected major role for atlastin-1 in the function of sensory neurons and identifies HSN I and SPG3A as allelic disorders. |
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