Submission Details

EGR2, historically known as Krox-20, was first reported in relation to semidominant Charcot-Marie-Tooth Disease in 1998 (Warner et al., PMID: 9537424). The majority of known mutations show autosomal dominant inheritance, however at least two reported cases show autosomal recessive inheritance. More than 20 unique missense variants have been reported in the literature, mostly concentrated in the zinc finger domains. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in over 25 probands and over 10 publications (PMIDs: 9537424, 11523566, 17717711, 31852952, 26204789, 20513111, 32896048, 30481651, 27159987, 30843326). There is additionally a significant amount of segregation evidence, with a total summed LOD score of 5.62 over four families. The majority of these probands have adult-onset demyelinating forms of the disorder (labeled as CMT1D) with mild-moderate symptoms; however, early-onset forms with more severe symptoms (labeled as Dejerine-Sottas neuropathy or congenital hypomyelinating neuropathy) and axonal forms (labeled as CMT2) are also included in the general spectrum of this curation (PMIDs: 10371530, 26204789). More genetic evidence is available to review in the literature. The mechanism for disease varies by inheritance pattern. In the dominant form, missense variants in one of three zinc finger domains interfere with DNA binding and decrease the activity of wildtype DNM2 via inappropriate interactions with cofactors. The resulting severity is roughly correlated with the amount of residual DNA binding for a dominant negative effect. Recessive variants located in the R1 domain disallow the ability for the protein to bind and be repressed by NAB proteins, resulting in a loss of function and decreased amount of DNA binding (Warner et al. 1999, PMID: 10369870). This gene-disease relationship is also supported by several types of experimental evidence. Both a knock-in model harboring the recessive Ile268Asn variant and a hypomorphic model of the dominant forms both recapitulated the major phenotypes of the human disorder, including neuropathy, immature Schwann cells, severe hypomyelination, and cranial nerve involvement. Functional studies and protein interactions additionally demonstrate EGR2's importance to myelination, with MPZ activation and expression severely affected by mutant co-expression. In summary, EGR2 is DEFINITIVELY associated with semidominant Charcot-Marie-Tooth Disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.