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Search for mutations in the EGR2 corepressor proteins, NAB1 and NAB2, in human peripheral neuropathies
Koen Venken1, Emilio Di Maria, Emilia Bellone
1Molecular Genetics Department, Flanders Interuniversity Institute for Biotechnology (VIB), Born-Bunge Foundation (BBS), University of Antwerp (UIA), Antwerpen, Belgium.
Abstract:
EGR2/Krox-20, a Cys2-His2 zinc finger transcription factor, plays an essential role in the regulation of myelination in the peripheral nervous system. Dominant and recessive mutations in EGR2 are associated with peripheral myelinopathies, such as Charcot-Marie-Tooth disease type 1, Dejerine-Sottas syndrome, and congenital hypomyelinating neuropathy. One recessive mutation (I268N) is known to affect the inhibitory domain that binds the NAB transcriptional corepressors, NAB1 and NAB2. This mutation abolishes the interaction of EGR2 with the NAB corepressors and thereby increases transcriptional activity. Therefore, we hypothesized that mutations in the EGR2-interacting domains of NAB1 and NAB2 might be associated with the pathogenesis of inherited peripheral neuropathies in currently unexplained cases. However, screening 87 such cases failed to identify any disease-causing mutations within the EGR2-interacting domains of either NAB1 or NAB2. A further mutation analysis of the complete coding regions of NAB1 and NAB2 in these genomic DNA samples did not uncover any disease-causing mutation. Therefore, our analysis indicates that mutations in the human NABI and NAB2 genes are most likely not involved in the pathogenesis of peripheral neuropathies.
Insights
Mutations in NAB1 and NAB2 genes are not linked to inherited peripheral neuropathies. This study investigated EGR2-interacting domains in 87 cases, finding no disease-causing mutations, ruling out these genes in disease pathogenesis.
Area of Science:
- Neuroscience
- Genetics
Background:
- Early growth response 2 (EGR2/Krox-20) is crucial for peripheral nervous system myelination.
- Mutations in EGR2 cause peripheral myelinopathies like Charcot-Marie-Tooth disease.
- A specific EGR2 mutation (I268N) disrupts binding to NAB1 and NAB2 corepressors, increasing transcriptional activity.
Purpose of the Study:
- To investigate if mutations in the EGR2-interacting domains of NAB1 and NAB2 are associated with unexplained inherited peripheral neuropathies.
- To screen for disease-causing mutations in NAB1 and NAB2 in patients with peripheral neuropathies.
Main Methods:
- Screening of 87 patients with unexplained peripheral neuropathies.
- Mutation analysis of EGR2-interacting domains of NAB1 and NAB2.
- Comprehensive mutation analysis of the complete coding regions of NAB1 and NAB2.
Main Results:
- No disease-causing mutations were identified in the EGR2-interacting domains of NAB1 or NAB2 in the screened patient cohort.
- Further analysis of the complete coding regions of NAB1 and NAB2 also failed to reveal any pathogenic mutations.
Conclusions:
- Mutations in the human NAB1 and NAB2 genes are unlikely to be a cause of inherited peripheral neuropathies.
- This study effectively rules out NAB1 and NAB2 as major genetic contributors to the pathogenesis of these conditions.