Leo Gotoh1, Ken Inoue1, Guy Helman2, Sara Mora3, Kiran Maski4, Janet S Soul4, Miriam Bloom5, Sarah H Evans6, Yu-Ichi Goto1, Ljubica Caldovic7, Grace M Hobson8, Adeline Vanderver9. 1. Department of Mental Retardation and Birth Defects Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan. 2. Department of Neurology, Children's National Medical Center, Washington, DC, USA. 3. Nemours Biomedical Research, Alfred I. duPont Hospital for Children, Wilmington, DE, USA. 4. Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA. 5. Department of Pediatrics, Children's National Medical Center, Washington, DC, USA. 6. Department of Physical Medicine and Rehabilitation, Children's National Medical Center, Washington, DC, USA. 7. Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA. 8. 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. 9. 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.
Abstract
OBJECTIVE: 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. METHODS: We describe two independent Pelizaeus-Merzbacher-like disease families with a novel promoter region mutation and updated in vitro functional assays. RESULTS: 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. INTERPRETATION: 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.
OBJECTIVE: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. METHODS: We describe two independent Pelizaeus-Merzbacher-like disease families with a novel promoter region mutation and updated in vitro functional assays. RESULTS: A novel GJC2 mutation (c.-170A>G) in the promoter region was identified in Pelizaeus-Merzbacher-like diseasepatients. In vitro functional assays using humanGJC2 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. INTERPRETATION: 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.
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