EGR2 – Charcot-Marie-Tooth disease type 3

Early growth response 2 (EGR2) is a zinc-finger transcription factor essential for peripheral nerve myelination. Heterozygous missense mutations in EGR2 have been identified in patients with Dejerine-Sottas neuropathy (Charcot-Marie-Tooth disease type 3), a severe early-onset demyelinating neuropathy characterized by slowed nerve conduction, onion bulb formation, and variable cranial nerve involvement. Functional studies in vitro and in vivo demonstrate that pathogenic variants dominantly impair EGR2 DNA-binding and transcriptional activation of key myelin genes, correlating with disease severity.

Genetic evidence supports an autosomal dominant inheritance for most EGR2-related CMT3 cases, with at least 7 probands across 4 unrelated families: one de novo c.1075C>T (p.Arg359Trp) in a DSS patient ([PMID:10371530]), one de novo c.1232A>G (p.Asp411Gly) in an early-onset DSN case ([PMID:31852952]), two unrelated DSN patients with recurrent c.1075C>T (p.Arg359Trp) ([PMID:11523566]), and a recessive family with three siblings homozygous for c.791C>T (p.Pro264Leu) ([PMID:32896048]). Segregation of the recessive variant in three affected sibs further strengthens causality.

All reported pathogenic alleles are missense substitutions clustered in or near the zinc-finger DNA-binding domains. The c.1075C>T (p.Arg359Trp) variant is recurrent and accounts for multiple DSN cases. No truncating or splice variants have been associated with CMT3.

Functional assays reveal that zinc-finger mutations reduce EGR2 affinity for canonical DNA targets and decrease transactivation of peripheral myelin protein enhancers. Luciferase reporter studies of p.Asp411Gly show impaired activation of a PMP22 enhancer element ([PMID:31852952]), while DNA-binding assays demonstrate a direct correlation between residual binding and clinical severity ([PMID:10369870]). A Krox20(I268F) mouse model recapitulates human hypomyelinating neuropathy, confirming that disrupted EGR2–NAB corepressor interactions lead to biphasic demyelination ([PMID:18524893]).

No conflicting evidence has been reported that refutes the EGR2–CMT3 association. Taken together, multiple independent probands, familial segregation, and concordant functional and animal data provide strong support for a pathogenic role of dominant EGR2 missense mutations in Charcot-Marie-Tooth disease type 3. Genetic testing for EGR2 variants is clinically useful for diagnosis, prognostication, and genetic counseling.

Key take-home: Heterozygous missense mutations in EGR2 consistently impair transcriptional regulation of myelin genes, leading to a definitive diagnosis of CMT3 and guiding patient management.

References

• Neurology • 1999 • Novel missense mutation in the early growth response 2 gene associated with Dejerine-Sottas syndrome phenotype. PMID:10371530
• Scientific reports • 2019 • A de novo EGR2 variant, c.1232A>G p.Asp411Gly, causes severe early-onset Charcot-Marie-Tooth Neuropathy Type 3 (Dejerine-Sottas Neuropathy). PMID:31852952
• Neurogenetics • 2001 • EGR2 mutation R359W causes a spectrum of Dejerine-Sottas neuropathy. PMID:11523566
• European journal of neurology • 2020 • Bi-allelic mutations in EGR2 cause autosomal recessive demyelinating neuropathy by disrupting the EGR2-NAB complex. PMID:32896048
• Human molecular genetics • 1999 • Functional consequences of mutations in the early growth response 2 gene (EGR2) correlate with severity of human myelinopathies. PMID:10369870
• The Journal of neuroscience • 2008 • Disruption of Krox20-Nab interaction in the mouse leads to peripheral neuropathy with biphasic evolution. PMID:18524893

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