Bi-allelic mutations in EGR2 cause autosomal recessive demyelinating neuropathy by disrupting the EGR2-NAB complex
| Autor: | Samuel I. Pascual-Pascual, Vincenzo Lupo, Carmen Espinós, John Svaren, Sneha S. Komath, Teresa Sevilla, Megan S Schnitzler, Seongsik Won, Marina Frasquet |
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| Rok vydání: | 2020 |
| Předmět: |
Genetic counseling
medicine.disease_cause 03 medical and health sciences symbols.namesake 0302 clinical medicine Charcot-Marie-Tooth Disease Medicine Missense mutation Animals Humans 030212 general & internal medicine Allele Gene Early Growth Response Protein 2 Genetics Sanger sequencing Zinc finger Mutation business.industry Homozygote EGR2 NAB autosomal recessive demyelinating neuropathy scoliosis Neurology symbols Neurology (clinical) Age of onset business 030217 neurology & neurosurgery Transcription Factors |
| Zdroj: | EUROPEAN JOURNAL OF NEUROLOGY r-IIS La Fe. Repositorio Institucional de Producción Científica del Instituto de Investigación Sanitaria La Fe instname |
| ISSN: | 1468-1331 1351-5101 |
| Popis: | 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 of EGR2 were 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 the EGR2 gene. 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. |
| Databáze: | OpenAIRE |
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