PMID- 31852952
OWN - NLM
STAT- MEDLINE
DCOM- 20201109
LR  - 20221207
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 9
IP  - 1
DP  - 2019 Dec 18
TI  - A de novo EGR2 variant, c.1232A > G p.Asp411Gly, causes severe early-onset 
      Charcot-Marie-Tooth Neuropathy Type 3 (Dejerine-Sottas Neuropathy).
PG  - 19336
LID - 10.1038/s41598-019-55875-4 [doi]
LID - 19336
AB  - 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.
FAU - Grosz, Bianca R
AU  - Grosz BR
AUID- ORCID: 0000-0002-6926-0551
AD  - Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, NSW, 
      Australia. bgro4046@uni.sydney.edu.au.
AD  - Sydney Medical School, University of Sydney, Sydney, NSW, Australia. 
      bgro4046@uni.sydney.edu.au.
FAU - Golovchenko, Natasha B
AU  - Golovchenko NB
AD  - Department of Human Genetics, University of Michigan Medical School, Ann Arbor, 
      MI, USA.
FAU - Ellis, Melina
AU  - Ellis M
AD  - Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, NSW, 
      Australia.
FAU - Kumar, Kishore
AU  - Kumar K
AUID- ORCID: 0000-0003-3482-6962
AD  - Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
AD  - Molecular Medicine Laboratory, Concord Repatriation General Hospital, Concord, 
      NSW, Australia.
AD  - Department of Neurology, Concord Repatriation General Hospital, Concord, NSW, 
      Australia.
FAU - Nicholson, Garth A
AU  - Nicholson GA
AD  - Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, NSW, 
      Australia.
AD  - Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
AD  - Molecular Medicine Laboratory, Concord Repatriation General Hospital, Concord, 
      NSW, Australia.
AD  - Department of Neurology, Concord Repatriation General Hospital, Concord, NSW, 
      Australia.
FAU - Antonellis, Anthony
AU  - Antonellis A
AUID- ORCID: 0000-0002-5820-3156
AD  - Department of Human Genetics, University of Michigan Medical School, Ann Arbor, 
      MI, USA.
AD  - Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, 
      USA.
FAU - Kennerson, Marina L
AU  - Kennerson ML
AUID- ORCID: 0000-0003-3332-5074
AD  - Northcott Neuroscience Laboratory, ANZAC Research Institute, Concord, NSW, 
      Australia. marina.kennerson@sydney.edu.au.
AD  - Sydney Medical School, University of Sydney, Sydney, NSW, Australia. 
      marina.kennerson@sydney.edu.au.
AD  - Molecular Medicine Laboratory, Concord Repatriation General Hospital, Concord, 
      NSW, Australia. marina.kennerson@sydney.edu.au.
LA  - eng
GR  - NS073748/U.S. Department of Health & Human Services | NIH | National 
      Institute of Neurological Disorders and Stroke (NINDS)/International
PT  - Case Reports
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20191218
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (EGR2 protein, human)
RN  - 0 (Early Growth Response Protein 2)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Age of Onset
MH  - Amino Acid Sequence
MH  - Base Sequence
MH  - Child
MH  - Child, Preschool
MH  - Computer Simulation
MH  - Early Growth Response Protein 2/chemistry/*genetics
MH  - Female
MH  - *Genetic Predisposition to Disease
MH  - Hereditary Sensory and Motor Neuropathy/diagnostic 
      imaging/*genetics/pathology/physiopathology
MH  - Humans
MH  - Magnetic Resonance Imaging
MH  - Male
MH  - Middle Aged
MH  - Mutation/*genetics
MH  - Neural Conduction
MH  - Pedigree
MH  - Protein Domains
MH  - Schwann Cells/metabolism
MH  - Transcription, Genetic
MH  - Transcriptional Activation/genetics
MH  - Exome Sequencing
PMC - PMC6920433
COIS- The authors declare no competing interests.
EDAT- 2019/12/20 06:00
MHDA- 2020/11/11 06:00
PMCR- 2019/12/18
CRDT- 2019/12/20 06:00
PHST- 2019/10/02 00:00 [received]
PHST- 2019/12/03 00:00 [accepted]
PHST- 2019/12/20 06:00 [entrez]
PHST- 2019/12/20 06:00 [pubmed]
PHST- 2020/11/11 06:00 [medline]
PHST- 2019/12/18 00:00 [pmc-release]
AID - 10.1038/s41598-019-55875-4 [pii]
AID - 55875 [pii]
AID - 10.1038/s41598-019-55875-4 [doi]
PST - epublish
SO  - Sci Rep. 2019 Dec 18;9(1):19336. doi: 10.1038/s41598-019-55875-4.