J Med Genet 39:e81 doi:10.1136/jmg.39.12.e81
  • Online mutation report

Frequency of mutations in the early growth response 2 gene associated with peripheral demyelinating neuropathies

  1. N Vandenberghe1,2,
  2. M Upadhyaya3,
  3. A Gatignol2,
  4. L Boutrand1,
  5. M Boucherat2,
  6. G Chazot1,
  7. A Vandenberghe1,2,
  8. P Latour
  1. 1Laboratoire de Génétique Moléculaire Humaine, Université Claude Bernard, Lyon 1, France
  2. 2Unité de Neurogénétique Moléculaire, Laboratoire de Biochimie, Hôpital de l’Antiquaille, Hospices Civils de Lyon, France
  3. 3Institute of Medical Genetics, University of Wales College of Medicine, Cardiff, Wales, UK
  1. Correspondence to:
 Dr N Vandenberghe, Laboratoire de Génétique Moléculaire Humaine, Université Claude Bernard, 8 Avenue Rockefeller, 69373 Lyon Cedex 08, France;

    Hereditary motor and sensory neuropathies (HMSN) comprise a wide clinical spectrum of related disorders with defects in peripheral nerve myelination. More than 250 distinct mutations of the peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ/P0), and connexin 32 (Cx32/GJB1) genes have been reported in patients diagnosed with different forms of hereditary motor and sensory neuropathies, such as Charcot-Marie-Tooth disease (CMT), Dejerine-Sottas syndrome (DSS), congenital hypomyelination (CH), and hereditary neuropathy with liability to pressure palsies (HNPP). To date, some 20 linked CMT loci and nine genes have been identified. Gene products include structural proteins (PMP22, MPZ), a gap junction protein (Cx32), and a transcription factor (EGR2). Recently, point mutations in the early growth response 2 (EGR2) gene, located on human chromosome 10q21.1-q22.1, have been associated with hereditary neuropathies.1

    The gene for EGR2 spans 4.3 kb, contains two coding exons,2 and is part of a multigene family encoding Cys2His2 type zinc finger proteins3 and may play a role in the regulation of cellular proliferation.4 EGR2 is a Schwann cell transcription factor that binds DNA through three zinc finger domains and is thought to regulate the expression of late myelin genes such as MPZ and myelin basic protein, thus playing a key role in myelogenesis.5

    Human EGR2 is homologous to the mouse Krox20 gene,6 which is part of a transcriptional cascade involved in the development and segmentation of the hindbrain. Homozygous mice knocked out for Krox20 display abnormal rhombomere segmentation and neuronal migration in the developing hindbrain, resulting in anatomical abnormalities of the cranial nerves.7 Furthermore, mice homozygous for a targeted mutation deleting a major part of the gene including the entire zinc finger domain die shortly after birth.5 Surviving Krox20-/- mice show a trembling phenotype, have hypomyelination …