Novel missense mutation in the early growth response 2 gene associated with Dejerine-Sottas syndrome phenotype.
BACKGROUND
Mutations in the early growth response 2 (EGR2) gene have recently been found in patients with congenital hypomyelinating neuropathy and Charcot-Marie-Tooth type 1 (CMT1) disease.


OBJECTIVE
To determine the frequency of EGR2 mutations in patients with a diagnosis of CMT1, Dejerine-Sottas syndrome (DSS), or unspecified peripheral neuropathies.


METHODS
Fifty patients and 70 normal control subjects were screened.


RESULTS
A de novo missense mutation (Arg359Trp) in the alpha-helix of the first zinc-finger domain of the EGR2 transcription factor was identified in a patient diagnosed with a clinical phenotype consistent with DSS. This patient had a motor median nerve conduction velocity of 8 m/s. A sural nerve biopsy showed a severe loss of myelinated and unmyelinated fibers, evidence for demyelination, numerous classic onion bulbs, and focally folded myelin sheaths. DSS is a severe, childhood-onset demyelinating peripheral neuropathy initially thought to be inherited as an autosomal recessive trait. However, several dominant heterozygous mutations in the peripheral myelin protein 22 (PMP22) gene and dominant mutations in the peripheral myelin protein zero (MPZ) gene, both in the heterozygous and homozygous state, have been reported in patients with DSS.


CONCLUSIONS
Hereditary peripheral neuropathies represent a spectrum of disorders due to underlying defects in myelin structure or formation.
Timmerman
V
V
Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology and Laboratory of Neurogenetics, Born-Bunge Foundation, University of Antwerp, Belgium.
De Jonghe
P
P
Ceuterick
C
C
De Vriendt
E
E
Löfgren
A
A
Nelis
E
E
Warner
L E
LE
Lupski
J R
JR
Martin
J J
JJ
Van Broeckhoven
C
C
D000595:Amino Acid Sequence; D001483:Base Sequence; D004252:DNA Mutational Analysis; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics*; D051767:Early Growth Response Protein 2; D015417:Hereditary Sensory and Motor Neuropathy / Q000235:genetics*; D006801:Humans; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D010641:Phenotype; D013497:Sural Nerve / Q000648:ultrastructure; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics*
D017931:DNA Primers; D004268:DNA-Binding Proteins; C497326:EGR2 protein, human; D051767:Early Growth Response Protein 2; D014157:Transcription Factors