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Mol Genet Metab. 2014 Mar;111(3):393-398. doi: 10.1016/j.ymgme.2013.12.001. Epub 2013 Dec 16.

GJC2 promoter mutations causing Pelizaeus-Merzbacher-like disease.

Author information

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.

KEYWORDS:

GJC2; Glia; Leukodystrophy; Myelin; Pelizaeus–Merzbacher

PMID:
24374284
PMCID:
PMC4183365
DOI:
10.1016/j.ymgme.2013.12.001
[Indexed for MEDLINE]
Free PMC Article

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