PMLD1 and SPG44 are caused by autosomal recessive variants in the GJC2gene encoding the gap junction protein connexin47 (Cx47). Gap junctions (GJ) are specialized channels between apposed cells allowing direct metabolic and electrical communication. Distinct connexins are expressed in unique cell types in the peripheral and central nervous system; the specificity of this expression underlies the critical roles of each of these cells in neurological functions. The nervous system expresses up to 12 of the 21 connexin family members. Connexin47 is highly expressed in oligodendrocytes, which play an essential role for proper myelination. To date, at least 45 different variants in the coding region of GJC2have been associated with recessively inherited CNS disease. These include missense, nonsense, and frameshift mutations. Two promoter mutations c.-167A>G and c.-170A>G and one mutation in the 5’ noncoding region at a predicted highly conserved splice site have also been identified. These pathogenic variants result in mislocalization of Cx47, activation of the unfolded protein response (UPR) or differential interaction with other connexin isoforms.
LMPH1C is caused by autosomal dominant inheritance of the GJC2gene, but it is unclear what role the GJC2gene plays in the lymphatic system and how mutations cause this condition. Ferrell et al. (2010) hypothed that the identified heterozygous mutations in the GJC2gene (S48L, R260C) associated with LMPH1C might result in impaired channel activity, which could cause impaired coordination of pulsatile lymphatic flow.
Genetic testing will be done by sequence analysis of the entire coding region of GJC2, including the noncoding exon 1, first. If only one pathogenic variant is found, gene-targeted deletion/duplication analysis will be performed.
GJC2