MCM3AP in recessive Charcot-Marie-Tooth neuropathy and mild intellectual disability

  • Brain. 2017 Aug 1;140(8):2093-2103. doi: 10.1093/brain/awx138.
Emil Ylikallio  1  2 ,  Rosa Woldegebriel  1 ,  Manuela Tumiati  3 ,  Pirjo Isohanni  1  4 ,  Monique M Ryan  5  6  7 ,  Zornitza Stark  5 ,  Maie Walsh  5 ,  Sarah L Sawyer  8 ,  Katrina M Bell  5 ,  Alicia Oshlack  5 ,  Paul J Lockhart  5  7  9 ,  Mariia Shcherbii  1 ,  Alejandro Estrada-Cuzcano  10 ,  Derek Atkinson  10 ,  Taila Hartley  8 ,  Martine Tetreault  11  12 ,  Inge Cuppen  13 ,  W Ludo van der Pol  14 ,  Ayse Candayan  15 ,  Esra Battaloglu  15 ,  Yesim Parman  16 ,  Koen L I van Gassen  17 ,  Marie-José H van den Boogaard  17 ,  Kym M Boycott  8 ,  Liisa Kauppi  3 ,  Albena Jordanova  10 ,  Tuula Lönnqvist  4 ,  Henna Tyynismaa  1  18
Affiliations
  • 1. Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland.
  • 2. Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland.
  • 3. Research Programs Unit, Genome-Scale Biology, University of Helsinki, 00290 Helsinki, Finland.
  • 4. Department of Child Neurology, Children's Hospital and Pediatric Research Center, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland.
  • 5. Murdoch Children's Research Institute, Melbourne, Victoria, 3052, Australia.
  • 6. Royal Children's Hospital, Melbourne, Victoria, 3052, Australia.
  • 7. Department of Paediatrics, The University of Melbourne, Melbourne, Victoria, 3052, Australia.
  • 8. Department of Genetics and Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, K1H 8L1, Canada.
  • 9. Bruce Lefroy Centre, Murdoch Childrens Research Institute, Melbourne, Victoria, 3052, Australia.
  • 10. Molecular Neurogenomics Group, VIB Department of Molecular Genetics, University of Antwerp, 2610 Antwerpen, Belgium.
  • 11. Department of Human Genetics, McGill University, Montreal, QC H3A 1B1, Canada.
  • 12. McGill University and Genome Quebec Innovation Center, Montreal, QC H3A 1A4, Canada.
  • 13. Department of Paediatric Neurology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
  • 14. Brain Centre Rudolf Magnus, Department of Neurology and Neurosurgery, University Medical Centre Utrecht, 3508 Utrecht, The Netherlands.
  • 15. Bogazici University, Department of Molecular Biology and Genetics, Istanbul, Turkey.
  • 16. Istanbul University, Istanbul Medical School, Department of Neurology, Istanbul, Turkey.
  • 17. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
  • 18. Department of Medical and Clinical Genetics, University of Helsinki, 00290 Helsinki, Finland.
PMID: 28633435 DOI: 10.1093/brain/awx138
Abstract

Defects in mRNA export from the nucleus have been linked to various neurodegenerative disorders. We report mutations in the gene MCM3AP, encoding the germinal center associated nuclear protein (GANP), in nine affected individuals from five unrelated families. The variants were associated with severe childhood onset primarily axonal (four families) or demyelinating (one family) Charcot-Marie-Tooth neuropathy. Mild to moderate intellectual disability was present in seven of nine affected individuals. The affected individuals were either compound heterozygous or homozygous for different MCM3AP variants, which were predicted to cause depletion of GANP or affect conserved Amino acids with likely importance for its function. Accordingly, fibroblasts of affected individuals from one family demonstrated severe depletion of GANP. GANP has been described to function as an mRNA export factor, and to suppress TDP-43-mediated motor neuron degeneration in flies. Thus our results suggest defective mRNA export from nucleus as a potential pathogenic mechanism of axonal degeneration in these patients. The identification of MCM3AP variants in affected individuals from multiple centres establishes it as a disease gene for childhood-onset recessively inherited Charcot-Marie-Tooth neuropathy with intellectual disability.

Keywords
Charcot-Marie-Tooth neuropathy; GANP; MCM3AP; intellectual disability; mRNA export.