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Hereditary Spastic Paraplegia Type 43 (SPG43) is Caused by Mutation in C19orf12 |
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| Authors: | Guida Landouré Peng‐Peng Zhu Charles M Lourenço Janel O Johnson Camilo Toro Katherine V Bricceno Carlo Rinaldi Katherine G Meilleur Modibo Sangaré Oumarou Diallo Tyler M Pierson Hiroyuki Ishiura Shoji Tsuji Nichole Hein John K Fink Marion Stoll Garth Nicholson Michael A Gonzalez Fiorella Speziani Alexandra Dürr Giovanni Stevanin Leslie G Biesecker for the NIH Intramural Sequencing Center John Accardi Dennis M D Landis William A Gahl Bryan J Traynor Wilson Marques Jr Stephan Züchner Craig Blackstone Kenneth H Fischbeck Barrington G Burnett |
| Institution: | 1. Service de Neurologie, Centre Hospitalier Universitaire du Point “G”, , Bamako, Mali;2. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, , Bethesda, Maryland;3. Department of Neuroscience and Behaviour Sciences, School of Medicine of Ribeir?o Preto, University of Sao Polo, , Sao Polo, Brazil;4. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, , Bethesda, Maryland;5. NIH Undiagnosed Diseases Program, NIH Common Fund, Office of the Director, National Institutes of Health, , Bethesda, Maryland;6. Tissue Injury Branch, National Institute of Nursing Research, National Institutes of Health, , Bethesda, Maryland;7. Department of Neurology, Graduate School of Medicine, University of Tokyo, , Tokyo, Japan;8. Department of Neurology, University of Michigan Medical School, , Ann Arbor, Michigan;9. Geriatric Research Education and Clinical Center, Ann Arbor Veterans Affairs Medical Center, University of Michigan, , Ann Arbor, Michigan;10. Northcott Neuroscience Laboratory, ANZAC Research Institute, University of Sydney, , Sydney, Australia;11. Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, , Miami, Florida;12. AP‐HP, Department of Genetics and Cytogenetics, Pitié‐Salpêtrière Hospital, , Paris, France;13. Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, INSERM/UPMC UMRS975, CNRS UMR7225, Pitié‐Salpêtrière Hospital, , Paris, France;14. Ecole Pratique des Hautes Etudes (EPHE), , Paris, France;15. Genetic Disease Research Branch and NIH Intramural Sequencing Center, National Institutes of Health, , Bethesda, Maryland |
| Abstract: | We report here the genetic basis for a form of progressive hereditary spastic paraplegia (SPG43) previously described in two Malian sisters. Exome sequencing revealed a homozygous missense variant (c.187G>C; p.Ala63Pro) in C19orf12, a gene recently implicated in neurodegeneration with brain iron accumulation (NBIA). The same mutation was subsequently also found in a Brazilian family with features of NBIA, and we identified another NBIA patient with a three‐nucleotide deletion (c.197_199del; p.Gly66del). Haplotype analysis revealed that the p.Ala63Pro mutations have a common origin, but MRI scans showed no brain iron deposition in the Malian SPG43 subjects. Heterologous expression of these SPG43 and NBIA variants resulted in similar alterations in the subcellular distribution of C19orf12. The SPG43 and NBIA variants reported here as well as the most common C19orf12 missense mutation reported in NBIA patients are found within a highly conserved, extended hydrophobic domain in C19orf12, underscoring the functional importance of this domain. |
| Keywords: | SPG43 NBIA C19orf12 hereditary spastic paraplegia |