2. Academic Validation
  3. PMPCA mutations cause abnormal mitochondrial protein processing in patients with non-progressive cerebellar ataxia

PMPCA mutations cause abnormal mitochondrial protein processing in patients with non-progressive cerebellar ataxia

  • Brain. 2015 Jun;138(Pt 6):1505-17. doi: 10.1093/brain/awv057.
Rebekah K Jobling 1,  Mirna Assoum 2,  Oleksandr Gakh 3,  Susan Blaser 4,  Julian A Raiman 1,  Cyril Mignot 5,  Emmanuel Roze 6,  Alexandra Dürr 7,  Alexis Brice 7,  Nicolas Lévy 8,  Chitra Prasad 9,  Tara Paton 10,  Andrew D Paterson 10,  Nicole M Roslin 10,  Christian R Marshall 10,  Jean-Pierre Desvignes 2,  Nathalie Roëckel-Trevisiol 2,  Stephen W Scherer 11,  Guy A Rouleau 12,  André Mégarbané 13,  Grazia Isaya 3,  Valérie Delague 14,  Grace Yoon 15
Affiliations

Affiliations

  • 1 1 Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
  • 2 2 Inserm, UMR_S 910, 13385, Marseille, France 3 Aix Marseille Université, GMGF, 13385, Marseille, France.
  • 3 4 Department of Paediatric and Adolescent Medicine and Mayo Clinic Children's Centre, Mayo Clinic, Rochester, MN, USA.
  • 4 5 Division of Neuroradiology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
  • 5 6 Département de Génétique, Unité de Génétique Clinique, APHP, Groupe Hospitalier Pitié-Salpêtrière; Centre de Référence Maladies Rares 'Déficiences Intellectuelles de Causes Rares'; Groupe de Recherche Clinique UPMC Univ Paris 06; Paris, France.
  • 6 7 Sorbonne Université, UPMC Univ Paris 06, UM 75, ICM, F-75013 Paris, France 8 Inserm, U 1127, ICM, F-75013 Paris, France 9 Cnrs, UMR 7225, ICM, F-75013 Paris, France 10 ICM, Paris, F-75013 Paris, France 11 AP-HP, Hôpital de la Salpêtrière, Département de Neurologie, F-75013, Paris, France.
  • 7 7 Sorbonne Université, UPMC Univ Paris 06, UM 75, ICM, F-75013 Paris, France 8 Inserm, U 1127, ICM, F-75013 Paris, France 9 Cnrs, UMR 7225, ICM, F-75013 Paris, France 10 ICM, Paris, F-75013 Paris, France 12 AP-HP, Hôpital de la Salpêtrière, Département de Génétique et Cytogénétique, F-75013, Paris, France.
  • 8 2 Inserm, UMR_S 910, 13385, Marseille, France 3 Aix Marseille Université, GMGF, 13385, Marseille, France 13 Département de Génétique Médicale, Hôpital d'Enfants de la Timone, AP-HM, Marseille, France.
  • 9 14 Medical Genetics Program, Department of Pediatrics, London Health Sciences Centre, London, Ontario, Canada.
  • 10 15 The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
  • 11 15 The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada 16 McLaughlin Centre and Department of Molecular Genetics, University of Toronto.
  • 12 17 Montreal Neurological Institute and Hospital and Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
  • 13 18 Unité de Génétique Médicale and Laboratoire Associé Inserm UMR S_910, Faculté de Médecine, Université Saint Joseph, Beirut, Lebanon 19 Institut Jérôme Lejeune, Paris, France.
  • 14 2 Inserm, UMR_S 910, 13385, Marseille, France 3 Aix Marseille Université, GMGF, 13385, Marseille, France [email protected] [email protected].
  • 15 1 Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada 20 Division of Neurology, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada [email protected] [email protected].
PMID: 25808372 DOI: 10.1093/brain/awv057
Abstract

Non-progressive cerebellar ataxias are a rare group of disorders that comprise approximately 10% of static infantile encephalopathies. We report the identification of mutations in PMPCA in 17 patients from four families affected with cerebellar ataxia, including the large Lebanese family previously described with autosomal recessive cerebellar ataxia and short stature of Norman type and localized to chromosome 9q34 (OMIM #213200). All patients present with non-progressive cerebellar ataxia, and the majority have intellectual disability of variable severity. PMPCA encodes α-MPP, the alpha subunit of mitochondrial processing peptidase, the primary Enzyme responsible for the maturation of the vast majority of nuclear-encoded mitochondrial proteins, which is necessary for life at the cellular level. Analysis of lymphoblastoid cells and fibroblasts from patients homozygous for the PMPCA p.Ala377Thr mutation and carriers demonstrate that the mutation impacts both the level of the alpha subunit encoded by PMPCA and the function of mitochondrial processing peptidase. In particular, this mutation impacts the maturation process of frataxin, the protein which is depleted in Friedreich ataxia. This study represents the first time that defects in PMPCA and mitochondrial processing peptidase have been described in association with a disease phenotype in humans.

Keywords

PMPCA; ataxia; cerebellar atrophy; mitochondrial processing peptidase; mitochondrial protein processing; non-progressive.

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