title: GJC2 promoter mutations causing Pelizaeus-Merzbacher-like disease.
abstract: Pelizaeus-Merzbacher-like disease is a rare hypomyelinating leukodystrophy caused by autosomal recessive mutations in GJC2, encoding a gap junction protein essential for production of a mature myelin sheath. A previously identified GJC2 mutation (c.-167A>G) in the promoter region is hypothesized to disrupt a putative SOX10 binding site; however, the lack of additional mutations in this region and contradictory functional data have limited the interpretation of this variant.
  
  
  
  We describe two independent Pelizaeus-Merzbacher-like disease families with a novel promoter region mutation and updated in vitro functional assays.
  
  
  
  A novel GJC2 mutation (c.-170A>G) in the promoter region was identified in Pelizaeus-Merzbacher-like disease patients. In vitro functional assays using human GJC2 promoter constructs demonstrated that this mutation and the previously described c.-167A>G mutation similarly diminished the transcriptional activity driven by SOX10 and the binding affinity for SOX10.
  
  
  
  These findings support the role of GJC2 promoter mutations in Pelizaeus-Merzbacher-like disease. GJC2 promoter region mutation screening should be included in the evaluation of patients with unexplained hypomyelinating leukodystrophies.
authors.affiliation: Department of Mental Retardation and Birth Defects Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Leo
authors.initials: L
authors.lastname: Gotoh
authors.affiliation: Department of Mental Retardation and Birth Defects Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Department of Neurology, Children's National Medical Center, Washington, DC, USA.
authors.forename: Guy
authors.initials: G
authors.lastname: Helman
authors.affiliation: Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, DE, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Mora
authors.affiliation: Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Kiran
authors.initials: K
authors.lastname: Maski
authors.affiliation: Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Janet S
authors.initials: JS
authors.lastname: Soul
authors.affiliation: Department of Pediatrics, Children's National Medical Center, Washington, DC, USA.
authors.forename: Miriam
authors.initials: M
authors.lastname: Bloom
authors.affiliation: Department of Physical Medicine and Rehabilitation, Children's National Medical Center, Washington, DC, USA.
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Evans
authors.affiliation: Department of Mental Retardation and Birth Defects Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Yu-Ichi
authors.initials: YI
authors.lastname: Goto
authors.affiliation: Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA.
authors.forename: Ljubica
authors.initials: L
authors.lastname: Caldovic
authors.affiliation: Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, DE, USA; Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA; Department of Biological Sciences, University of Delaware, Newark, DE, USA.
authors.forename: Grace M
authors.initials: GM
authors.lastname: Hobson
authors.affiliation: Department of Neurology, Children's National Medical Center, Washington, DC, USA; Department of Pediatrics, Children's National Medical Center, Washington, DC, USA; Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA. Electronic address: avanderv@childrensnational.org.
authors.forename: Adeline
authors.initials: A
authors.lastname: Vanderver
mesh_terms: D000328:Adult; D001665:Binding Sites; D002648:Child; D017630:Connexins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009186:Myelin Sheath / Q000473:pathology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D055757:SOXE Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D017630:Connexins; C527923:SOX10 protein, human; D055757:SOXE Transcription Factors; C427305:connexin 47
keywords: GJC2; Glia; Leukodystrophy; Myelin; Pelizaeus–Merzbacher