ClinVar Genomic variation as it relates to human health

In a Japanese female with a mild Pelizaeus-Merzbacher-like disorder (HLD2; 608804) who was previously reported by Nezu et al. (1996), Osaka et al. (2010) identified a homozygous -167A-G mutation within the proximal GJC2 promoter that segregated with the disorder. The patient's healthy, second-cousin parents were heterozygous for the mutation, which was not found in 122 normal Japanese chromosomes. The mutation is located within a critical SOX10 binding site (site D) in the syntenic mouse Gjc2 proximal promoter and diminishes the consensus of the SOX binding sequence. Functional studies on the mouse promoter indicated that the -167A-G mutation abolishes SOX10 binding to the GJC2 promoter, resulting in a dramatic attenuation of GJC2 transcription. Combes et al. (2012) identified the -167A-G mutation in 7 patients with a disorder similar to that in the Japanese patient reported by Osaka et al. (2010). The mutation was homozygous in 5 patients from 4 unrelated families from the same area of south Tunisia and segregated with the disease in a consanguineous family with 2 affected members; it was also found in 2 unrelated patients from the Mediterranean area in compound heterozygosity with another mutation in the GJC2 gene that had been identified by Henneke et al. (2008) in patients with HLD2. The mutation was not found in 212 healthy individuals from the same geographic regions. Functional studies in COS-7 and HEK293 cells demonstrated a higher luciferase expression with the mutated promoter than with the wildtype, suggesting a possible difference in transcription factor recruitment. Using a new reporter luciferase assay in a human glioblastoma cell line (U138), Gotoh et al. (2014) demonstrated that the -167A-G mutation reduced transcriptional activity compared to wildtype in response to SOX10 (602229). The findings suggested that the mutation disrupts SOX10 binding, resulting in a decrease in the GJC2 expression that is important for the maintenance of myelinating oligodendrocytes. (less)