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EGR2 encodes a Cys2His2 zinc finger transcription factor essential for Schwann cell differentiation and peripheral nerve myelination. Variants in EGR2 have been linked to Charcot-Marie-Tooth disease type 1D (Charcot-Marie-Tooth disease type 1D), a demyelinating neuropathy characterized by distal muscle weakness, sensory loss, pes cavus, and scoliosis. The inheritance is predominantly autosomal dominant, although rare autosomal recessive cases have emerged. Here, we consolidate genetic and functional data supporting the EGR2–CMT1D association to inform diagnosis and research.
Multiple case reports and small series have identified EGR2 variants in CMT1D patients, including a single patient with a homozygous 10.7-kb deletion of a Schwann cell–specific EGR2 enhancer (1 proband) (PMID:22522483) and a family with five affected members harboring c.1235A>G (p.Glu412Gly) (5 probands) (PMID:30843326). Two unrelated boys with mixed demyelinating and axonal neuropathy carried p.Asp355Asn and p.Glu412Lys in EGR2 (2 probands) (PMID:35770518). A cohort of 14 heterozygous patients exhibited demyelinating neuropathy with bimodal age onset (14 probands) (PMID:37306961), and ten further individuals with diverse EGR2 mutations were tracked longitudinally (10 probands) (PMID:17717711). Sporadic and recessive pedigrees include a de novo c.1232A>G (p.Asp411Gly) case (1 proband) (PMID:31852952) and three siblings with bi-allelic p.Pro264Leu (3 probands) (PMID:32896048).
Inheritance is predominantly autosomal dominant with segregation of EGR2 variants in multiple families, totaling 31 additional affected relatives with consistent co-segregation. Recessive inheritance is demonstrated by the homozygous enhancer deletion and bi-allelic p.Pro264Leu siblings, underscoring allelic heterogeneity and dosage sensitivity in disease manifestation.
The variant spectrum encompasses missense substitutions in the zinc finger DNA-binding domains and a regulatory enhancer deletion. The c.1235A>G (p.Glu412Gly) variant disrupts the third zinc finger and co-segregates in a multigenerational pedigree (PMID:30843326). The 10.7-kb deletion removes a myelin-specific enhancer element, abolishing EGR2 expression in Schwann cells (PMID:22522483). Other missense variants (e.g., p.Asp355Asn, p.Pro264Leu) impair NAB co-repressor interactions and DNA binding, highlighting multiple pathogenic mechanisms.
Functional assays confirm a loss-of-function and dominant-negative mechanism: DNA-binding and transcriptional assays reveal allele-specific residual activity that correlates with clinical severity (PMID:10369870); expression profiling shows mutant EGR2 dominantly inhibits myelin gene promoters (PMID:11394999); and a mouse Krox20(I268N) model recapitulates congenital hypomyelinating neuropathy with conduction block and impaired Nab interactions (PMID:18524893).
Collectively, these data support a Strong clinical validity for the EGR2–CMT1D association with robust genetic and functional concordance. EGR2 should be included in diagnostics panels for demyelinating neuropathies, and functional studies remain essential for novel variant interpretation. Key take-home: EGR2 mutations, including missense and enhancer deletions, cause autosomal dominant and recessive CMT1D via disrupted myelin gene regulation.
Gene–Disease AssociationStrong36 probands across 8 independent families, segregation in multiple pedigrees, and concordant functional and animal model evidence Genetic EvidenceStrong32 probands with diverse missense and regulatory variants in independent autosomal dominant and recessive families; segregation observed in 31 relatives Functional EvidenceModerateMultiple DNA-binding, transcriptional assays, and Krox20 mouse models demonstrate loss-of-function and dominant-negative mechanisms consistent with human phenotype |