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GJC2 promoter mutations causing Pelizaeus-Merzbacher-like disease
Leo Gotoh1, Ken Inoue1, Guy Helman2
1Department of Mental Retardation and Birth Defects Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
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.
Insights
New GJC2 promoter mutations cause Pelizaeus-Merzbacher-like disease by disrupting SOX10 binding. This finding supports screening GJC2 promoter regions in patients with unexplained hypomyelinating leukodystrophies.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Pelizaeus-Merzbacher-like disease (PMLD) is a rare hypomyelinating leukodystrophy.
- Mutations in GJC2, encoding a gap junction protein, cause PMLD by impairing myelin sheath formation.
- A previously identified GJC2 promoter mutation (c.-167A>G) was hypothesized to affect SOX10 binding, but its role remained unclear.
Purpose of the Study:
- To investigate novel GJC2 promoter mutations in PMLD.
- To functionally characterize the impact of GJC2 promoter mutations on SOX10 binding and transcriptional activity.
Main Methods:
- Identified a novel GJC2 promoter mutation (c.-170A>G) in two independent PMLD families.
- Performed in vitro functional assays using human GJC2 promoter constructs.
- Assessed the effect of mutations on SOX10-driven transcriptional activity and SOX10 binding affinity.
Main Results:
- The novel c.-170A>G GJC2 promoter mutation was identified in PMLD patients.
- Both c.-170A>G and the previously reported c.-167A>G mutations similarly reduced SOX10 transcriptional activity.
- These mutations decreased the binding affinity for SOX10.
Conclusions:
- GJC2 promoter mutations play a significant role in Pelizaeus-Merzbacher-like disease.
- Screening the GJC2 promoter region is recommended for diagnosing unexplained hypomyelinating leukodystrophies.
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