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Bi-allelic mutations inEGR2cause autosomal recessive demyelinating neuropathy by disrupting the EGR2-NAB complex

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Autores de CIPF

Participantes ajenos a CIPF

  • Won, S
  • Frasquet, M
  • Schnitzler, MS
  • Komath, SS
  • Pascual-Pascual, SI
  • Svaren, J
  • Sevilla, T

Grupos de Investigación

Abstract

Background and purpose Mutations in the early growth response 2 gene (EGR2) cause demyelinating, but also axonal, neuropathies differing in severity and age of onset. Except for one family, all reported cases have autosomal dominant inheritance and mutations are localized within the three zinc finger (ZNF) DNA-binding domain. The aim of this study was to provide a clinical and molecular analysis of a novel recessive mutation in EGR2. Methods Clinical and electrophysiological assessments of three affected patients, from a consanguineous family, were performed. Genetic analyses ofEGR2were carried out by Sanger sequencing. Functional effects of clinical recessive mutations were assessed using a mammalian two-hybrid assay. Results A novel missense mutation (c.791C>T; p.P264L) in the homozygous state was detected outside the ZNF domains of theEGR2gene. Three affected siblings presented with distal demyelinating polyneuropathy with severe sensory loss, progressive thoracolumbar scoliosis and trigeminal neuralgia. Respiratory compromise and cranial nerve dysfunction were also found. Our data indicate that the p.P264L mutation prevents interaction of EGR2 transcription factor with NAB corepressors, suggesting that a disruption of the NAB-EGR2 protein interactions can result in dramatic neuropathy. Conclusion Mutations in, or next to, the R1 domain of EGR2 should be considered with extreme caution for genetic counseling, since these could cause a severe neuropathy with an autosomal recessive manner of transmission.

Datos de la publicación

ISSN/ISSNe:
1351-5101, 1468-1331

EUROPEAN JOURNAL OF NEUROLOGY  WILEY

Tipo:
Article
Páginas:
2662-2667
PubMed:
32896048

Citas Recibidas en Web of Science: 4

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Keywords

  • autosomal recessive; demyelinating neuropathy; EGR2; NAB; scoliosis

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