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

Rebekah K. Jobling, Mirna Assoum, Oleksandr Gakh, Susan Blaser, Julian A. Raiman, Cyril Mignot, Emmanuel Roze, Alexandra Dürr, Alexis Brice, Nicolas Lévy, Chitra Prasad, Tara Paton, Andrew D. Paterson, Nicole M. Roslin, Christian R. Marshall, Jean Pierre Desvignes, Nathalie Roëckel-Trevisiol, Stephen W. Scherer, Guy A. Rouleau, André MégarbanéGrazia Isaya, Valérie Delague, Grace Yoon

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1505-1517
Number of pages13
Issue number6
StatePublished - Jun 1 2015


  • Ataxia
  • Cerebellar atrophy
  • Mitochondrial processing peptidase
  • Mitochondrial protein processing
  • Non-progressive

ASJC Scopus subject areas

  • Clinical Neurology


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