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

• Published in: Scientific reports Vol. 9; no. 1; pp. 19336 - 8
• Main Authors: Grosz, Bianca R., Golovchenko, Natasha B., Ellis, Melina, Kumar, Kishore, Nicholson, Garth A., Antonellis, Anthony, Kennerson, Marina L.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.12.2019; Nature Publishing Group
• Subjects: 38/109; 38/5; 45; 45/23; 59/57; 631/208/1516; 631/208/737; 631/378/1959; Adolescent; Adult; Age; Age of Onset; Amino Acid Sequence; Ankle; Base Sequence; Biopsy; Charcot-Marie-Tooth disease; Child; Child, Preschool; Computer Simulation; Congenital diseases; Early Growth Response Protein 2 - chemistry; Early Growth Response Protein 2 - genetics; Egr-2 protein; Female; Fingers & toes; Genes; Genetic Predisposition to Disease; Genotype & phenotype; Hereditary Sensory and Motor Neuropathy - diagnostic imaging; Hereditary Sensory and Motor Neuropathy - genetics; Hereditary Sensory and Motor Neuropathy - pathology; Hereditary Sensory and Motor Neuropathy - physiopathology; Heterogeneity; Humanities and Social Sciences; Humans; Laboratories; Magnetic Resonance Imaging; Male; Middle Aged; multidisciplinary; Mutation - genetics; Neural Conduction; Pathogens; Pedigree; Peripheral neuropathy; Protein Domains; Proteins; Repatriation; Schwann Cells - metabolism; Science; Science (multidisciplinary); Transcription factors; Transcription, Genetic; Transcriptional Activation - genetics; Whole Exome Sequencing
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-55875-4

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.