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Mutations in POLR3A and POLR3B are a major cause of hypomyelinating leukodystrophies with or without dental abnormalities and/or hypogonadotropic hypogonadism
  1. Hussein Daoud1,
  2. Martine Tétreault1,2,
  3. William Gibson3,
  4. Kether Guerrero4,
  5. Ana Cohen3,
  6. Janina Gburek-Augustat5,
  7. Matthis Synofzik6,7,
  8. Bernard Brais2,
  9. Cathy A Stevens8,
  10. Rocio Sanchez-Carpintero9,
  11. Cyril Goizet10,
  12. Sakkubai Naidu11,
  13. Adeline Vanderver12,
  14. Geneviève Bernard4
  1. 1Center of Excellence in Neuroscience of Université de Montréal, CRCHUM, Montreal, Quebec, Canada
  2. 2Neurogenetics of Motion Laboratory, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
  3. 3Department of Medical Genetics Child and Family Research Institute, University of British Columbia, Vancouver, Canada
  4. 4Departments of Pediatrics, Neurology and Neurosurgery, Division of Pediatric Neurology, Montreal Children's Hospital, McGill University Heath Center, Montreal, Quebec, Canada
  5. 5Department of Neuropaediatrics, Developmental Neurology and Social Paediatrics, University Childreńs Hospital Tübingen, Germany
  6. 6Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
  7. 7German Research Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Germany
  8. 8Department of Pediatrics, University of Tennessee College of Medecine, Chattonooga, Tennessee, USA
  9. 9Pediatric Neurology Unit, Department of Pediatrics, University Clinic of Navarra, Pamplona, Spain
  10. 10Department of Medical Genetics, Hospital Pellegrin, CHU Bordeaux and Laboratoire Maladies Rares: Génétique et Métabolisme (MRGM), Université Bordeaux Segalen, Bordeaux, France
  11. 11Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, Maryland, USA
  12. 12Department of Neurology, Children's National Medical Center, Washington D.C., USA
  1. Correspondence to Geneviève Bernard, Montreal Children's Hospital, Room A-506, 2300 Tupper, Montreal, Quebec H3H 1P3, Canada; genevieve.bernard{at}


Background Leukodystrophies are a heterogeneous group of inherited neurodegenerative disorders characterised by abnormal central nervous system white matter. Mutations in POLR3A and POLR3B genes were recently reported to cause four clinically overlapping hypomyelinating leukodystrophy phenotypes. Our aim was to investigate the presence and frequency of POLR3A and POLR3B mutations in patients with genetically unexplained hypomyelinating leukodystrophies with typical clinical and/or radiologic features of Pol III-related leukodystrophies.

Methods The entire coding region and the flanking exon/intron boundaries of POLR3A and/or POLR3B genes were amplified and sequenced in 14 patients.

Results Recessive mutations in POLR3A or POLR3B were uncovered in all 14 patients. Eight novel mutations were identified in POLR3A: six missenses, one nonsense, and one frameshift mutation. Seven patients carried compound heterozygous mutations in POLR3B, of whom six shared the common mutation in exon 15 (p.V523E). Seven novel mutations were identified in POLR3B: four missenses, two splice sites, and one intronic mutation.

Conclusions To date, our group has described 37 patients, of whom 27 have mutations in POLR3A and 10 in POLR3B, respectively. Altogether, our results further support the proposal that POLR3A and POLR3B mutations are a major cause of hypomyelinating leukodystrophies and suggest that POLR3A mutations are more frequent.

  • Leukodystrophy
  • Hypomyelination
  • POLR3A
  • POLR3B

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