Hereditary Spastic Paraplegia Type 43 (SPG43) is Caused by Mutation in C19orf12

Authors

  • Guida Landouré,

    Corresponding author
    1. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
    • Service de Neurologie, Centre Hospitalier Universitaire du Point “G”, Bamako, Mali
    Search for more papers by this author
  • Peng-Peng Zhu,

    1. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
    Search for more papers by this author
  • Charles M. Lourenço,

    1. Department of Neuroscience and Behaviour Sciences, School of Medicine of Ribeirão Preto, University of Sao Polo, Sao Polo, Brazil
    Search for more papers by this author
  • Janel O. Johnson,

    1. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland
    Search for more papers by this author
  • Camilo Toro,

    1. NIH Undiagnosed Diseases Program, NIH Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland
    Search for more papers by this author
  • Katherine V. Bricceno,

    1. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
    Search for more papers by this author
  • Carlo Rinaldi,

    1. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
    Search for more papers by this author
  • Katherine G. Meilleur,

    1. Tissue Injury Branch, National Institute of Nursing Research, National Institutes of Health, Bethesda, Maryland
    Search for more papers by this author
  • Modibo Sangaré,

    1. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
    Search for more papers by this author
  • Oumarou Diallo,

    1. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
    Search for more papers by this author
  • Tyler M. Pierson,

    1. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
    2. NIH Undiagnosed Diseases Program, NIH Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland
    Search for more papers by this author
  • Hiroyuki Ishiura,

    1. Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
    Search for more papers by this author
  • Shoji Tsuji,

    1. Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
    Search for more papers by this author
  • Nichole Hein,

    1. Department of Neurology, University of Michigan Medical School, Ann Arbor, Michigan
    Search for more papers by this author
  • John K. Fink,

    1. Department of Neurology, University of Michigan Medical School, Ann Arbor, Michigan
    2. Geriatric Research Education and Clinical Center, Ann Arbor Veterans Affairs Medical Center, University of Michigan, Ann Arbor, Michigan
    Search for more papers by this author
  • Marion Stoll,

    1. Northcott Neuroscience Laboratory, ANZAC Research Institute, University of Sydney, Sydney, Australia
    Search for more papers by this author
  • Garth Nicholson,

    1. Northcott Neuroscience Laboratory, ANZAC Research Institute, University of Sydney, Sydney, Australia
    Search for more papers by this author
  • Michael A. Gonzalez,

    1. Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida
    Search for more papers by this author
  • Fiorella Speziani,

    1. Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida
    Search for more papers by this author
  • Alexandra Dürr,

    1. AP-HP, Department of Genetics and Cytogenetics, Pitié-Salpêtrière Hospital, Paris, France
    2. Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, INSERM/UPMC UMRS975, CNRS UMR7225, Pitié-Salpêtrière Hospital, Paris, France
    Search for more papers by this author
  • Giovanni Stevanin,

    1. AP-HP, Department of Genetics and Cytogenetics, Pitié-Salpêtrière Hospital, Paris, France
    2. Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, INSERM/UPMC UMRS975, CNRS UMR7225, Pitié-Salpêtrière Hospital, Paris, France
    3. Ecole Pratique des Hautes Etudes (EPHE), Paris, France
    Search for more papers by this author
  • Leslie G. Biesecker,

    1. Genetic Disease Research Branch and NIH Intramural Sequencing Center, National Institutes of Health, Bethesda, Maryland
    Search for more papers by this author
  • for the NIH Intramural Sequencing Center,

  • John Accardi,

    1. NIH Undiagnosed Diseases Program, NIH Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland
    Search for more papers by this author
  • Dennis M. D. Landis,

    1. NIH Undiagnosed Diseases Program, NIH Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland
    Search for more papers by this author
  • William A. Gahl,

    1. NIH Undiagnosed Diseases Program, NIH Common Fund, Office of the Director, National Institutes of Health, Bethesda, Maryland
    Search for more papers by this author
  • Bryan J. Traynor,

    1. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland
    Search for more papers by this author
  • Wilson Marques Jr,

    1. Department of Neuroscience and Behaviour Sciences, School of Medicine of Ribeirão Preto, University of Sao Polo, Sao Polo, Brazil
    Search for more papers by this author
  • Stephan Züchner,

    1. Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida
    Search for more papers by this author
  • Craig Blackstone,

    1. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
    Search for more papers by this author
  • Kenneth H. Fischbeck,

    1. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
    Search for more papers by this author
  • Barrington G. Burnett

    1. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
    Search for more papers by this author

  • Contract grant sponsors: NIH/NINDS Intramural Research Funds (1ZIA NS002974-13); NHGRI; NIH (R01NS072248, R01NS054132); l'Agence Nationale pour la Recherche (SPAX); VERUM Foundation and Association Strümpell-Lorrain.

  • Communicated by Lars Bertram

Correspondence to: Guida Landouré, Service de Neurologie, Centre Hospitalier Universitaire du Point “G”, Point “G”, Bamako, PO Box: 333, Mali. E-mail: landoureg@ninds.nih.gov

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.

Ancillary