GJC2 – Hypomyelinating leukodystrophy type 2

Hypomyelinating leukodystrophy type 2 (HLD2, MONDO:0012125) is an autosomal recessive hypomyelinating disorder characterized by infantile‐onset nystagmus, global developmental delay, ataxia, and motor impairment. It is caused by biallelic mutations in GJC2 (HGNC:17494) encoding the gap junction protein connexin 47 (Cx47). Clinical presentation overlaps with Pelizaeus–Merzbacher-like disease, with variable severity and, in some pedigrees, intrafamilial phenotypic heterogeneity manifesting as hereditary spastic paraplegia (PMID:37915394). Brain MRI consistently demonstrates diffuse hypomyelination.

Genetic evidence includes over 16 unrelated probands from at least 14 families identified through targeted or exome sequencing (PMID:18094336). Variant spectrum comprises missense (e.g., c.760G>A (p.Val254Met) PMID:35794704, c.778G>A (p.Glu263Lys) PMID:22669416), nonsense, frameshift, splice, and promoter mutations (c.-167A>G) PMID:21959080. Autosomal recessive inheritance is confirmed by segregation in consanguineous families, with affected siblings homozygous or compound heterozygous for pathogenic alleles.

Segregation analysis in multiple families demonstrated co-segregation of homozygous or compound heterozygous GJC2 variants with disease, while parents were heterozygous carriers. In the initial report, a novel c.760G>A (p.Val254Met) PMID:35794704 mutation was homozygous in two affected siblings, confirming autosomal recessive transmission.

Functional assays reveal that PMLD-associated GJC2 missense mutations (p.Pro87Ser, p.Tyr269Asp, p.Met283Thr) accumulate in the endoplasmic reticulum and fail to form functional gap junction channels, as evidenced by absent Lucifer Yellow and neurobiotin transfer and loss of electrical coupling in cell models PMID:17344063. Further studies showed that several mutants (e.g., p.Gly236Ser, p.Thr398Ile) disrupt both Cx47/Cx47 and Cx47/Cx43 channels PMID:23544880, and promoter mutations abolish SOX10‐driven transcriptional activation of GJC2 PMID:20695017.

In primary oligodendrocytes, PMLD1 mutants (p.Pro87Ser, p.Tyr269Asp, p.Met283Thr) activate the unfolded protein response and apoptotic pathways, supporting a toxic gain‐of‐function component to pathogenesis PMID:35276347. In vivo, transgenic expression of human Cx32 under the PLP promoter rescues CNS demyelination in Cx32/Cx47 double‐knockout mice, demonstrating the cell‐autonomous requirement of oligodendrocyte gap junctions for myelin maintenance PMID:25524707.

Together, the evidence fulfills criteria for a definitive gene–disease relationship. Biallelic GJC2 mutations impair oligodendrocyte gap junction connectivity, leading to dysmyelination. Genetic testing of GJC2 informs accurate diagnosis and carrier screening, while functional studies guide therapeutic strategies targeting protein trafficking and gap junction assembly.

References

• Genomics & informatics • 2022 • A novel mutation in GJC2 associated with hypomyelinating leukodystrophy type 2 disorder. PMID:35794704
• Neurology • 2008 • GJA12 mutations are a rare cause of Pelizaeus-Merzbacher-like disease. PMID:18094336
• Molecular and cellular neurosciences • 2007 • Loss-of-function GJA12/Connexin47 mutations cause Pelizaeus-Merzbacher-like disease. PMID:17344063
• The Biochemical journal • 2013 • The distribution and functional properties of Pelizaeus-Merzbacher-like disease-linked Cx47 mutations on Cx47/Cx47 homotypic and Cx47/Cx43 heterotypic gap junctions. PMID:23544880
• Molecular genetics and metabolism • 2011 • Promoter mutation is a common variant in GJC2-associated Pelizaeus-Merzbacher-like disease. PMID:21959080
• Molecular and cellular neurosciences • 2022 • Activation of the unfolded protein response by Connexin47 mutations associated with Pelizaeus-Merzbacher-like disease. PMID:35276347
• European journal of human genetics : EJHG • 2013 • Expanded spectrum of Pelizaeus-Merzbacher-like disease: literature revision and description of a novel GJC2 mutation in an unusually severe form. PMID:22669416
• Annals of neurology • 2010 • Disrupted SOX10 regulation of GJC2 transcription causes Pelizaeus-Merzbacher-like disease. PMID:20695017

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