title: PMPCA mutations cause abnormal mitochondrial protein processing in patients with non-progressive cerebellar ataxia.
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.
authors: 1 Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
authors: Rebekah K
authors: RK
authors: Jobling
authors: 2 Inserm, UMR_S 910, 13385, Marseille, France 3 Aix Marseille Université, GMGF, 13385, Marseille, France.
authors: Mirna
authors: M
authors: Assoum
authors: 4 Department of Paediatric and Adolescent Medicine and Mayo Clinic Children's Centre, Mayo Clinic, Rochester, MN, USA.
authors: Oleksandr
authors: O
authors: Gakh
authors: 5 Division of Neuroradiology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors: Susan
authors: S
authors: Blaser
authors: 1 Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
authors: Julian A
authors: JA
authors: Raiman
authors: 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.
authors: Cyril
authors: C
authors: Mignot
authors: 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.
authors: Emmanuel
authors: E
authors: Roze
authors: 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.
authors: Alexandra
authors: A
authors: Dürr
authors: 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.
authors: Alexis
authors: A
authors: Brice
authors: 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.
authors: Nicolas
authors: N
authors: Lévy
authors: 14 Medical Genetics Program, Department of Pediatrics, London Health Sciences Centre, London, Ontario, Canada.
authors: Chitra
authors: C
authors: Prasad
authors: 15 The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
authors: Tara
authors: T
authors: Paton
authors: 15 The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
authors: Andrew D
authors: AD
authors: Paterson
authors: 15 The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
authors: Nicole M
authors: NM
authors: Roslin
authors: 15 The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
authors: Christian R
authors: CR
authors: Marshall
authors: 2 Inserm, UMR_S 910, 13385, Marseille, France 3 Aix Marseille Université, GMGF, 13385, Marseille, France.
authors: Jean-Pierre
authors: JP
authors: Desvignes
authors: 2 Inserm, UMR_S 910, 13385, Marseille, France 3 Aix Marseille Université, GMGF, 13385, Marseille, France.
authors: Nathalie
authors: N
authors: Roëckel-Trevisiol
authors: 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.
authors: Stephen W
authors: SW
authors: Scherer
authors: 17 Montreal Neurological Institute and Hospital and Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
authors: Guy A
authors: GA
authors: Rouleau
authors: 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.
authors: André
authors: A
authors: Mégarbané
authors: 4 Department of Paediatric and Adolescent Medicine and Mayo Clinic Children's Centre, Mayo Clinic, Rochester, MN, USA.
authors: Grazia
authors: G
authors: Isaya
authors: 2 Inserm, UMR_S 910, 13385, Marseille, France 3 Aix Marseille Université, GMGF, 13385, Marseille, France grace.yoon@utoronto.ca valerie.delague@univ-amu.fr.
authors: Valérie
authors: V
authors: Delague
authors: 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 grace.yoon@utoronto.ca valerie.delague@univ-amu.fr.
authors: Grace
authors: G
authors: Yoon
mesh_terms: D000328:Adult; D002648:Child; D006801:Humans; D007861:Lebanon; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D021122:Protein Subunits / Q000235:genetics* / Q000378:metabolism; D013132:Spinocerebellar Degenerations / Q000235:genetics* / Q000378:metabolism*; D055815:Young Adult; D000096122:Mitochondrial Processing Peptidase
chemical_list: D008666:Metalloendopeptidases; D024101:Mitochondrial Proteins; D021122:Protein Subunits; D000096122:Mitochondrial Processing Peptidase
keywords: PMPCA; ataxia; cerebellar atrophy; mitochondrial processing peptidase; mitochondrial protein processing; non-progressive