GJB1 – X-linked Charcot-Marie-Tooth disease type 1

X-linked Charcot-Marie-Tooth disease type 1 (CMTX1) is a dominantly inherited peripheral neuropathy caused by pathogenic variants in GJB1, encoding connexin-32 (Cx32). Affected males typically present in the second decade with distal muscle wasting, steppage gait, hyporeflexia, sensory loss, and pes cavus, whereas females exhibit milder or variable phenotypes often detected by electrophysiology. Subclinical and transient central nervous system involvement, including reversible white matter lesions and transient stroke-like episodes, is reported in a subset of patients.

Genetic studies demonstrate an X-linked dominant inheritance with no male-to-male transmission. A de novo c.23C>T (p.Thr8Ile) variant was identified in a patient with negative family history, confirming sporadic occurrence ([PMID:10938190]). In a large Swiss pedigree, 19 affected relatives segregated a c.260C>T (p.Pro87Leu) missense change ([PMID:12614935]). Multi-family screening across nine pedigrees revealed segregation of missense, nonsense, frameshift, and small deletion mutations in eight families, including variants at codons 15, 60, 63, 208, and 215 ([PMID:8162049]).

Large cohort sequencing of 1483 suspected CMT patients identified GJB1 variants in 88 unrelated pedigrees, uncovering 23 novel and 36 known mutations with strong gender differences in onset and severity ([PMID:29998508]). The spectrum includes >100 unique missense substitutions, multiple loss-of-function alleles (nonsense, frameshift, gene deletions), and non-coding promoter mutations, with recurrent founder variants such as p.Val95Met in Korean and Hungarian populations.

Functional analyses reveal loss of Cx32 gap junction coupling as the predominant mechanism. Transgenic mice with a frameshift mutation (175fs) show absent Cx32 protein and no toxic gain of function, supporting haploinsufficiency ([PMID:10411340]). Schwann-cell-specific expression of human Cx32 in null mice rescues demyelination, demonstrating that Cx32 loss alone is sufficient to cause neuropathy ([PMID:15703409]). Cellular assays in oocytes and mammalian cells show impaired channel conductance, altered gating, intracellular retention, dominant-negative effects, and stress granule formation for numerous missense and truncating mutants.

No studies have formally refuted the GJB1–CMTX1 association; variable penetrance in females reflects X-inactivation rather than conflicting evidence. Collectively, the genetic and experimental concordance over three decades establishes a definitive gene-disease relationship. GJB1 mutation analysis is clinically actionable for diagnosis, carrier detection, and genetic counseling in CMTX1.

Key take-home: Pathogenic GJB1 variants cause CMTX1 via loss of connexin-32–mediated gap junctions in Schwann cells, yielding a definitive diagnostic target with established genetic and functional validation.

References

• Neurological sciences • 2000 • A new de novo mutation of the connexin-32 gene in a patient with X-linked Charcot-Marie-Tooth type 1 disease PMID:10938190
• Journal of the neurological sciences • 2003 • Phenotypic expression of a Pro 87 to Leu mutation in the connexin 32 gene in a large Swiss family with Charcot-Marie-Tooth neuropathy PMID:12614935
• Human molecular genetics • 1994 • Mutations in the connexin 32 gene in X-linked dominant Charcot-Marie-Tooth disease (CMTX1) PMID:8162049
• European journal of neurology • 2018 • Genetic and phenotypic profile of 112 patients with X-linked Charcot-Marie-Tooth disease type 1 PMID:29998508
• Journal of neuropathology and experimental neurology • 1999 • Studies in transgenic mice indicate a loss of connexin32 function in X-linked Charcot-Marie-Tooth disease PMID:10411340
• The Journal of neuroscience • 2005 • Transgenic expression of human connexin32 in myelinating Schwann cells prevents demyelination in connexin32-null mice PMID:15703409

Evidence Based Scoring (AI generated)