GJC2 – Hereditary Spastic Paraplegia Type 44

GJC2 encodes connexin-47 (Cx47), a gap junction protein expressed in oligodendrocytes. Autosomal recessive mutations in GJC2 are established causes of Pelizaeus-Merzbacher-like disease, and emerging evidence implicates biallelic variants in a milder phenotype, hereditary spastic paraplegia type 44 (SPG44).

Genetic evidence includes two unrelated homozygous variants in SPG44 patients: c.302G>T (p.Arg101Leu) identified in a patient with subclinical leukodystrophy showing predominant lower limb spasticity (PMID:25059390); and c.14G>T (p.Ser5Ile) segregating with disease in an Iranian family where the proband presented complicated HSP and siblings had hypomyelinating leukodystrophy (PMID:37915394).

Inheritance is autosomal recessive with co-segregation of GJC2 variants in affected members. No additional affected relatives with pure SPG44 phenotype beyond probands have been reported.

Functional studies of p.Arg101Leu in HeLa cells demonstrate formation of gap junction plaques similar to wild-type Cx47 but a 20-fold reduction in electrical coupling, while heterotypic coupling with Cx43 is preserved, supporting a partial loss-of-function mechanism (PMID:25059390).

Together, the genetic and electrophysiological data support a limited but consistent association between biallelic GJC2 variants and SPG44, mediated by reduced Cx47 channel opening efficiency. Additional segregation and functional studies could strengthen this link.

Key take-home: GJC2 should be included in diagnostic panels for autosomal recessive spastic paraplegia, especially when MRI shows hypomyelination.

References

• Journal of neurology • 2014 • A new mutation in GJC2 associated with subclinical leukodystrophy. PMID:25059390
• Molecular syndromology • 2023 • Description of Phenotypic Heterogeneity in a GJC2-Related Family and Literature Review. PMID:37915394

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