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

Autor: Anthony Antonellis, Melina Ellis, Garth A. Nicholson, Marina L. Kennerson, Kishore R. Kumar, Natasha Golovchenko, Bianca R. Grosz
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Male
0301 basic medicine
Proband
Pathology
Transcription
Genetic
Neural Conduction
lcsh:Medicine
0302 clinical medicine
Peripheral myelin protein 22
Medicine
Missense mutation
Age of Onset
Child
lcsh:Science
Multidisciplinary
medicine.diagnostic_test
Medical genetics
Middle Aged
Magnetic Resonance Imaging
Phenotype
Pedigree
medicine.anatomical_structure
Child
Preschool
Peripheral nervous system
Female
Adult
Transcriptional Activation
medicine.medical_specialty
Adolescent
Article
03 medical and health sciences
Protein Domains
Exome Sequencing
Humans
Computer Simulation
Genetic Predisposition to Disease
Amino Acid Sequence
Early Growth Response Protein 2
Nerve biopsy
Base Sequence
business.industry
lcsh:R
medicine.disease
030104 developmental biology
Peripheral neuropathy
Mutation
lcsh:Q
Schwann Cells
Age of onset
Hereditary Sensory and Motor Neuropathy
business
030217 neurology & neurosurgery
Zdroj: Scientific Reports, Vol 9, Iss 1, Pp 1-8 (2019)
Scientific Reports
ISSN: 2045-2322
Popis: 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.
Databáze: OpenAIRE
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