GJA12 mutations in children with recessive hypomyelinating leukoencephalopathy

Abstract

The identification of homozygous mutations predicting the synthesis of aberrant and truncated polypeptides, and their tight segregation with the disease in very large families, clearly demonstrate that the loss of Cx47 function is the cause of the disease. The phenotype of GJA12-related Pelizaeus-Merzbacher-like disease is fairly homogeneous and similar to that of Pelizaeus-Merzbacher disease. However, slower progression of symptoms, greater preservation of cognitive functions, and partial myelination of corticospinal tracts at MRI were distinctive features, which could help in the differential diagnosis.

Loss-of-function GJA12/Connexin47 mutations cause Pelizaeus–Merzbacher-like disease

“…The PMLD patients described to date (Uhlenberg et al 2004;Bugiani et al 2006) have similar phenotypes -nystagmus noted by 7 weeks, and impaired motor development noted by 15 months. Different genotypes -homozygous P128frameshift, M283T, G233S, or L278frameshift mutations, compound heterozygotes for P87S/P327frameshift or Y269D/ R237stop mutations -cause the same phenotype, including alleles that would be predicted to disrupt the protein (P128frameshift, R237stop, and L278frameshift, P327frameshift), as well as ones that may not (P87S, G233S, Y269D, and M283T).…”

“…(A) This is a schematic drawing of human Cx47 that illustrates the position and nature of mutations associated with PMLD; note the four missense mutations P87S, G233S, Y269D, and M283T, as well as P128frameshift, R237stop, and L278frameshift, P327frameshift (Uhlenberg et al 2004;Bugiani et al 2006). The positions of the transmembrane domains are based on the work of Yeager and Nicholson (Yeager and Nicholson 1996).…”

“…Although CNS myelination in Gja12/cx47-null mice is minimally affected (Menichella et al 2003;Odermatt et al 2003), recessive GJA12/Cx47 mutations cause a devastating dysmyelinating disease in humans, called Pelizaeus-Merzbacher-like disease (PMLD; (Uhlenberg et al 2004;Bugiani et al 2006). PMD itself is an X-linked dysmyelinating disorder caused by mutations in Proteolipid Protein 1 (PLP1), which encodes the main intrinsic membrane protein of CNS myelin (Garbern et al 1999).…”

“…PMLD patients are clinically similar to those with PMD, with nystagmus, spasticity, and ataxia, as well as widespread changes in CNS white matter by MRI imaging (Hudson et al 2004), but do not have PLP1 mutations. The clinical phenotype and MRI findings in patients with recessive GJA12/Cx47 mutations (Uhlenberg et al 2004;Bugiani et al 2006) provide provocative evidence that Cx47-mediated GJC is essential for the proper functioning of oligodendrocytes. We show here that Cx47 is expressed by oligodendrocytes in the primate brain and that recessive missense mutations in GJA12/Cx47 cause loss-of-function.…”

Expanded spectrum of Pelizaeus–Merzbacher-like disease: literature revision and description of a novel GJC2 mutation in an unusually severe form

“…3 To date, 25 different GJC2 mutant alleles, harbouring 9 missense, 10 frameshift, 3 nonsense, 1 microinsertion and 1 regulatory mutations have been reported in 54 PMLD1 patients belonging to 32 families. [4][5][6][7][8][9][10][11][12][13] In addition, another GJC2 missense mutation causing a milder phenotype, the spastic paraplegia autosomal recessive type 44 (SPG44) (MIM# 613206), has been reported in three members of a single family. 14 These findings suggest that this gene may give rise to a spectrum of disorders with different severity, in analogy with the PLP1 gene.…”