A de novo EGR2 variant, c.1232A > G p.Asp411Gly, causes severe early-onset Charcot-Marie-Tooth Neuropathy Type 3 (Dejerine-Sottas Neuropathy)

Abstract

EGR2 (early growth response 2) is a crucial transcription factor for the myelination of the peripheral nervous system. Mutations in EGR2 are reported to cause a heterogenous spectrum of peripheral neuropathy with wide variation in both severity and age of onset, including demyelinating and axonal forms of Charcot-Marie Tooth (CMT) neuropathy, Dejerine-Sottas neuropathy (DSN/CMT3), and congenital hypomyelinating neuropathy (CHN/CMT4E). Here we report a sporadic de novo EGR2 variant, c.1232A > G (NM_000399.5), causing a missense p.Asp411Gly substitution and discovered through whole-exome sequencing (WES) of the proband. The resultant phenotype is severe demyelinating DSN with onset at two years of age, confirmed through nerve biopsy and electrophysiological examination. In silico analyses showed that the Asp411 residue is evolutionarily conserved, and the p.Asp411Gly variant was predicted to be deleterious by multiple in silico analyses. A luciferase-based reporter assay confirmed the reduced ability of p.Asp411Gly EGR2 to activate a PMP22 (peripheral myelin protein 22) enhancer element compared to wild-type EGR2. This study adds further support to the heterogeneity of EGR2-related peripheral neuropathies and provides strong functional evidence for the pathogenicity of the p.Asp411Gly EGR2 variant. Charcot-Marie-Tooth (CMT) neuropathy is group of degenerative motor and sensory peripheral neuropathies which are clinically and genetically heterogenous. Pathogenic variants in over 90 genes cause CMT, and whole-exome sequencing (WES) is now an effective tool for screening known causative genes in unsolved CMT families. Pathogenic variants in the EGR2 gene (early growth response 2) cause a broad spectrum of peripheral neuropathy phenotypes. This includes two forms of severe early-onset peripheral neuropathy, Dejerine-Sottas neuropathy (DSN/CMT3) 1-3 and congenital hypomyelinating neuropathy (CHN/CMT4E) 4,5 , as well as adult-onset demyelinating CMT1D with mild-moderate symptoms 3-12 and variable-onset axonal CMT with varied symptom severity 13,14. EGR2 encodes a C 2 H 2-type zinc-finger transcription factor that regulates the expression of genes involved in the formation and maintenance of myelin, including GJB1 (gap junction beta 1), MPZ (myelin protein zero), MBP (myelin basic protein), MAG (myelin associated glycoprotein), PRX (periaxin), and PMP22 (peripheral myelin protein 22) 4,15-18. Approximately half of the reported disease-associated EGR2 variants are de novo and are associated with a severe phenotype 13. Here, we report a sporadic de novo EGR2 variant in the third zinc-finger domain, c.1232A > G p.Asp411Gly, discovered through WES candidate gene screening. This variant manifested as a severe DSN phenotype with early onset at two years of age.

Clinical and mutational spectrum of paediatric Charcot-Marie-Tooth disease in a large cohort of Chinese patients

“…The most common phenotypes for infantile-onset patients were DSS in our findings. Genetically, most cases are caused by a dominant or de novo mutation in the PMP22, MPZ or EGR2 genes (Gargaun et al, 2016;Grosz et al, 2019;Yoshimura et al, 2019). In addition to PMP22 mutations, variants in rare genes, e.g., EGR2, PRX, and FGD4 were found more frequently due to the introduction of NGS and WES, which was consistent with previous studies (Yoshimura et al, 2019).…”

Streptolysin S induces pronounced calcium-ion influx-dependent expression of immediate early genes encoding transcription factors

“…Interestingly, the IEGs investigated this study are also related to disorders of the central nervous system. For example, associations have been found between EGR1 and Alzheimer's disease 44 , EGR2 and Charcot-Marie-Tooth disease 45 – 47 , EGR3 and schizophrenia 48 – 50 , and c-Jun and Krox24 (EGR1) and Alzheimer's disease 51 . In nerve cells, the expression of IEGs encoding transcription factors, such as c-Fos and EGR1, is induced by an increase in intracellular Ca 2+ as a result of synaptic activity.…”

EGR2 gene‐linked hereditary neuropathies present with a bimodal age distribution at symptoms onset

“…Mutations in the Early-Growth Response 2 (EGR2) gene (OMIM #129010) provoke demyelinating Charcot-Marie-Tooth (CMT) disease type 1D (CMT1D, OMIM #607678), congenital hypomyelinating neuropathy type 1 (CHN1, OMIM #605253), Déjerine-Sottas syndrome (DSS, OMIM #145900), and axonal CMT (CMT2). [1][2][3][4][5][6][7][8][9][10][11] EGR2 gene encodes for a zinc finger (ZNF) transcription factor crucial for peripheral nervous system (PNS) myelination and it is hypothesized EGR2 gene mutations disrupt PNS myelination program, thus provoking a wide spectrum of demyelinating neuropathies ranging from early-onset severe variants such as CHN1 and DSS, to late-onset moderate variants such as CMT1D. [1][2][3][4][5][6][7][8][9][10][11] More recently, it has been shown that EGR2 gene mutations also provoke axonal CMT2-like neuropathies, indicating a role for EGR2 in axonal maintenance.…”

“…[1][2][3][4][5][6][7][8][9][10][11] EGR2 gene encodes for a zinc finger (ZNF) transcription factor crucial for peripheral nervous system (PNS) myelination and it is hypothesized EGR2 gene mutations disrupt PNS myelination program, thus provoking a wide spectrum of demyelinating neuropathies ranging from early-onset severe variants such as CHN1 and DSS, to late-onset moderate variants such as CMT1D. [1][2][3][4][5][6][7][8][9][10][11] More recently, it has been shown that EGR2 gene mutations also provoke axonal CMT2-like neuropathies, indicating a role for EGR2 in axonal maintenance. 12,13 EGR2 gene mutations causing demyelinating neuropathy were identified in 1998 and more than 25 different mutations have been described since then.…”