EGR2 – Charcot-Marie-Tooth Disease

Heterozygous mutations in the EGR2 transcription factor cause autosomal dominant Charcot-Marie-Tooth disease (CMT), characterized by peripheral demyelinating neuropathy and variable age of onset. Initial reports described a father–daughter pair carrying the p.Arg359Trp variant, with the proband exhibiting more severe features due to an additional GJB1 mutation (PMID:15947997). Subsequent family studies identified a p.Thr387Asn variant associated with a mild demyelinating phenotype in adult-onset CMT (PMID:22734907) and a p.Arg353Gly substitution uncovering asymptomatic demyelinating neuropathy upon vincristine challenge (PMID:22271166).

A case series of ten unrelated patients with diverse EGR2 missense mutations in zinc-finger domains confirmed a spectrum of demyelinating neuropathies, including de novo and dominant-negative alleles (10 patients) (PMID:17717711). Novel variants such as p.Arg381Leu were reported in a teen with combined peripheral and pyramidal signs (PMID:30889162). Rare recessive p.Pro264Leu homozygotes from a consanguineous pedigree presented with severe demyelinating neuropathy in three siblings (PMID:32896048), and two unrelated boys with p.Asp355Asn and p.Glu412Lys exhibited mixed demyelinating-axonal CMT features (PMID:35770518).

Population studies indicate that EGR2 mutations account for a small fraction of CMT cases (<1%), with most positive findings in clinical series achieving a detection rate of <5%. Segregation analyses demonstrated additional affected relatives in four instances, underscoring autosomal dominant inheritance with rare recessive exceptions.

Functional assays reveal that zinc-finger mutations such as p.Arg359Trp and p.Arg381His reduce DNA-binding affinity and fail to transactivate myelin gene promoters, including Cx32 and PMP22 enhancers (PMID:10369870). Mouse models harboring the I268N mutation recapitulate congenital hypomyelination and conduction block, confirming disruption of Egr2–Nab interactions as a disease mechanism (PMID:18524893).

Collectively, EGR2 fulfills ClinGen criteria for a strong gene–disease association based on at least 20 probands from 17 unrelated families with concordant segregation and variant-specific functional impairment. The genetic evidence is strong, and experimental data are moderate, supporting EGR2 as a diagnostic target in CMT panels. Ongoing discovery of novel alleles and animal models will refine genotype–phenotype correlations.

Key Take-home: Heterozygous EGR2 missense variants in zinc-finger domains cause autosomal dominant CMT through loss of transcriptional control of myelin genes, with strong genetic and moderate functional evidence guiding diagnostic testing.

References

• Neurogenetics • 2007 • Functional, histopathologic and natural history study of neuropathy associated with EGR2 mutations. PMID:17717711
• Human molecular genetics • 1999 • Functional consequences of mutations in the early growth response 2 gene (EGR2) correlate with severity of human myelinopathies. PMID:10369870
• Neurobiology of disease • 2008 • Disruption of Krox20-Nab interaction in the mouse leads to peripheral neuropathy with biphasic evolution. PMID:18524893
• Neurogenetics • 2005 • Two missense mutations of EGR2 R359W and GJB1 V136A in a Charcot-Marie-Tooth disease family. PMID:15947997
• Journal of the peripheral nervous system : JPNS • 2012 • A novel EGR2 mutation within a family with a mild demyelinating form of Charcot-Marie-Tooth disease. PMID:22734907
• Neurogenetics • 2012 • Vincristine exacerbates asymptomatic Charcot-Marie-Tooth disease with a novel EGR2 mutation. PMID:22271166
• Acta bio-medica : Atenei Parmensis • 2019 • Charcot-Marie-Tooth disease with pyramidal features due to a new mutation of EGR2 gene. PMID:30889162
• European journal of neurology • 2020 • Bi-allelic mutations in EGR2 cause autosomal recessive demyelinating neuropathy by disrupting the EGR2-NAB complex. PMID:32896048
• Clinical neuropathology • 2022 • EGR2-related mixed demyelinating and axonal Charcot-Marie-Tooth disease: An electrodiagnostic, nerve imaging, and histological study. PMID:35770518

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