Promoter mutation is a common variant in GJC2-associated Pelizaeus-Merzbacher-like disease

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Pelizaeus-Merzbacher-like disease (PMLD) is a rare neurological disorder characterized by impaired myelination.
• Clinical features include nystagmus, motor deficits, ataxia, and spasticity, often presenting in infancy.

Purpose of the Study:

• To identify the genetic cause of PMLD in consanguineous families with cerebral hypomyelination.
• To investigate the role of the GJC2 gene in PMLD pathogenesis.

Main Methods:

• Autozygosity mapping and SNP microarray analysis were used to identify linkage.
• Direct sequencing of the GJC2 gene, including promoter and non-coding regions, was performed.
• Haplotype analysis was conducted to assess common ancestry.

Main Results:

• Linkage to chromosome 1q42.13-1q42.2 was established.
• A novel GJC2 promoter mutation (c.-167A>G) in non-coding exon 1 was identified in affected individuals.
• This mutation was found in three families and may represent a founder mutation, accounting for approximately 29% of GJC2-PMLD cases.

Conclusions:

• The GJC2 promoter mutation is a significant cause of PMLD.
• Comprehensive GJC2 gene screening, including non-coding exon 1, is crucial for accurate PMLD diagnosis and to prevent diagnostic delays.