Brain Advance Access originally published online on March 5, 2008
Brain 2008 131(4):1078-1086; doi:10.1093/brain/awn026
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REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31
1Institute for Clinical Chemistry and Laboratory Diagnostics, University Hospital Jena, 2Department of Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Germany, 3Neurogenetics Group, Department of Molecular Genetics, VIB, University of Antwerp, Belgium, 4Center for Human Genetics, Duke University, Durham, NC, 5Athena Diagnostics Inc., Worcester, MA, USA, 6Department of Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, 7Department of Clinical Genetics, University Hospital Maastricht and Research Institute for Growth and Development (GROW), University of Maastricht, The Netherlands, 8Conway Institute of Biomolecular and Biomedical Research, University College Dublin, 9Department of Neurology, St Vincent's University Hospital and University College Dublin, Ireland, 10Department of Neurology, St Josef Hospital, Bochum, Germany, 11MRC-Holland, Amsterdam, The Netherlands, 12Miami Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA, 13Division of Neurology, Antwerp University Hospital, Antwerp, 14Department of Neurology, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Belgium, 15Department of Neurology, University of Ulm, 16Department of Neurology, University of Mainz, 17Department of Neurology, Ludwigs Maximilians University Munich and 18Department of Neurology, University of Kiel, Germany
Correspondence to: Stephan Züchner, MD, University of Miami Miller School of Medicine, Miami Institute for Human Genomics, Clinical Research Building, Room 810, 1120 N.W. 14th Street, Miami, FL 33136, USA E-mail: szuchner{at}med.miami.edu
Mutations in the receptor expression enhancing protein 1 (REEP1) have recently been reported to cause autosomal dominant hereditary spastic paraplegia (HSP) type SPG31. In a large collaborative effort, we screened a sample of 535 unrelated HSP patients for REEP1 mutations and copy number variations. We identified 13 novel and 2 known REEP1 mutations in 16 familial and sporadic patients by direct sequencing analysis. Twelve out of 16 mutations were small insertions, deletions or splice site mutations. These changes would result in shifts of the open-reading-frame followed by premature termination of translation and haploinsufficiency. Interestingly, we identified two disease associated variations in the 3'-UTR of REEP1 that fell into highly conserved micro RNA binding sites. Copy number variation analysis in a subset of 133 HSP index patients revealed a large duplication of REEP1 that involved exons 2–7 in an Irish family. Clinically most SPG31 patients present with a pure spastic paraplegia; rare complicating features were restricted to symptoms or signs of peripheral nerve involvement. Interestingly, the distribution of age at onset suggested a bimodal pattern with the appearance of initial symptoms of disease either before the age of 20 years or after the age of 30 years. The overall mutation rate in our clinically heterogeneous sample was 3.0%; however, in the sub-sample of pure HSP REEP1 mutations accounted for 8.2% of all patients. These results firmly establish REEP1 as a relatively frequent autosomal dominant HSP gene for which genetic testing is warranted. We also establish haploinsufficiency as the main molecular genetic mechanism in SPG31, which should initiate and guide functional studies on REEP1 with a focus on loss-of-function mechanisms. Our results should be valid as a reference for mutation frequency, spectrum of REEP1 mutations, and clinical phenotypes associated with SPG31.
Key Words: hereditary spastic paraplegia; SPG31; REEP1; haploinsufficiency; micro RNA
Abbreviations: HSP, hereditary spastic paraplegia; MLPA, multiplex ligation-dependent probe amplification; NCV, nerve conduction velocity; SPG, spastic paraplegia gene; REEP1, receptor expression enhancing protein 1
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Received November 26, 2007. Revised January 4, 2008. Accepted January 31, 2008.
*These authors contributed equally to this work.
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