Chapter 10 - Connexin Mutations in Pelizaeus–Merzbacher-Like Disease, Oculodentodigital Dysplasia and Related Diseases

Abstract

Central nervous system (CNS) glia and neurons express connexins, the proteins that form gap junctions in vertebrates. Mutations in three connexin genes, GJA1 , GJB1 and GJC2 , are associated with significant CNS disease. Recessive mutations in GJC2 , coding for connexin 47 (Cx47), cause Pelizaeus–Merzbacher-like disease type 1, characterized by nystagmus, cerebellar ataxia and spasticity, with abnormal myelination. Hereditary spastic paraparesis is also caused by a GJC2 mutation. Mutations in GJA1 , coding for Cx43, cause a dominant pleiotropic disorder, oculodentodigital dysplasia, characterized by oculofacial abnormalities (microphthalmia, syndactyly and dental abnormalities) and neurological manifestations, and recessive GJA1 mutations cause the related Hallermann–Streiff syndrome. This chapter describes the clinical phenotypes of GJC2- and GJA1 -associated disease, followed by a discussion of the distribution and physiological roles of connexins expressed by oligodendrocytes (e.g. Cx47, Cx32) and astrocytes (e.g. Cx26, Cx30, Cx43), and mechanisms by which mutations in GJC2 or GJA1 may lead to human disease.