Hereditary Spastic Paraplegia (HSP) comprises a group of neurodegenerative disorders characterized by progressive spasticity of the lower limbs and has fascinating clinical and pathophysiological overlap with amyotrophic lateral sclerosis (ALS), hereditary motor neuropathies, and axonal neuropathies. HSP is genetically heterogeneous with autosomal dominant, autosomal recessive, and X-linked forms. Genes have been identified for only 14 of the 30 reported HSP chromosomal loci. The identification and molecular characterization of additional HSP genes is key to improve our understanding of the underlying pathophysiology. Thus, we will strive to identify the underlying gene of the well-defined HSP locus on chromosome 19q (SPG12). We will have access to DNA samples from all known linked SPG12 families through collaborations with investigators in France (Dr Alexandra Durr), Italy (Dr. Antonio Orlacchio), and the UK (Dr. Evan Reid). An identified SPG12 gene will be included in our mutation screening and functional studies. The indispensable basis of our successful HSP genetic program has been the collection of HSP families over more than 15 years. This program has recently been moved with the principal investigators to the University of Miami. The expansion and clinical improvement of this collection is the basis of our genetic and molecular HSP research. Recently we have identified the underlying gene for the SPG31 locus, receptor expression enhancing protein 1 (REEP1), which appears to represent 6.5% of all HSP patients making it the third most common HSP gene after spastin and atlastin. We will clinically study the REEP1 families in more detail and screen for additional REEP1 mutations in a sample of 370 HSP patients collected by Dr. de Jonghe, University of Antwerp. Finally, we propose the molecular characterization of the mutations identified in the novel mitochondrial protein REEP1 and possibly in the SPG12 gene. Dr. Moraes is a world-renowned specialist for mitochondrial disease mechanisms and is a new investigator on this grant specifically to address the third aim. We strongly believe that only such an integrated approach - clinical, genetic, and molecular/functional - will yield significant progress in the understanding of HSP. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS054132-01A2
Application #
7382454
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Sutherland, Margaret L
Project Start
2007-12-15
Project End
2011-11-30
Budget Start
2007-12-15
Budget End
2008-11-30
Support Year
1
Fiscal Year
2008
Total Cost
$330,050
Indirect Cost
Name
University of Miami School of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Synofzik, Matthis; Helbig, Katherine L; Harmuth, Florian et al. (2018) De novo ITPR1 variants are a recurrent cause of early-onset ataxia, acting via loss of channel function. Eur J Hum Genet 26:1623-1634
Ozes, B; Karagoz, N; Schüle, R et al. (2017) PLA2G6 mutations associated with a continuous clinical spectrum from neuroaxonal dystrophy to hereditary spastic paraplegia. Clin Genet 92:534-539
Synofzik, Matthis; Smets, Katrien; Mallaret, Martial et al. (2016) SYNE1 ataxia is a common recessive ataxia with major non-cerebellar features: a large multi-centre study. Brain 139:1378-93
Mademan, Inès; Harmuth, Florian; Giordano, Ilaria et al. (2016) Multisystemic SYNE1 ataxia: confirming the high frequency and extending the mutational and phenotypic spectrum. Brain 139:e46
Schmidt, Wolfgang M; Rutledge, S Lane; Schüle, Rebecca et al. (2015) Disruptive SCYL1 Mutations Underlie a Syndrome Characterized by Recurrent Episodes of Liver Failure, Peripheral Neuropathy, Cerebellar Atrophy, and Ataxia. Am J Hum Genet 97:855-61
Caballero Oteyza, Andrés; Battalo?lu, Esra; Ocek, Levent et al. (2014) Motor protein mutations cause a new form of hereditary spastic paraplegia. Neurology 82:2007-16
Synofzik, Matthis; Gonzalez, Michael A; Lourenco, Charles Marques et al. (2014) PNPLA6 mutations cause Boucher-Neuhauser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum. Brain 137:69-77
Synofzik, Matthis; Haack, Tobias B; Kopajtich, Robert et al. (2014) Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration. Am J Hum Genet 95:689-97
Synofzik, Matthis; Schüle, Rebecca; Schulze, Martin et al. (2014) Phenotype and frequency of STUB1 mutations: next-generation screenings in Caucasian ataxia and spastic paraplegia cohorts. Orphanet J Rare Dis 9:57
Landouré, Guida; Zhu, Peng-Peng; Lourenço, Charles M et al. (2013) Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12. Hum Mutat 34:1357-60

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