SUMMARY:
miR-29a regulates PMP22 expression.
TITLE:
Post-transcriptional microRNA repression of PMP22 dose in severe Charcot-Marie-Tooth disease type 1
DESCRIPTION:
Copy number variation (CNV) may lead to pathological traits, and Charcot-Marie-Tooth disease type 1A (CMT1A), the commonest inherited peripheral neuropathy, is due to a genomic duplication encompassing the dosage-sensitive PMP22 gene. MicroRNAs act as repressors on post-transcriptional regulation of gene expression and in rodent models of CMT1A, overexpression of one such microRNA (miR-29a) has been shown to reduce the PMP22 transcript and protein level. Here we present genomic and functional…
CONTENT:
Brain. 2023 Jun 20:awad203. doi: 10.1093/brain/awad203. Online ahead of print.
ABSTRACT
Copy number variation (CNV) may lead to pathological traits, and Charcot-Marie-Tooth disease type 1A (CMT1A), the commonest inherited peripheral neuropathy, is due to a genomic duplication encompassing the dosage-sensitive PMP22 gene. MicroRNAs act as repressors on post-transcriptional regulation of gene expression and in rodent models of CMT1A, overexpression of one such microRNA (miR-29a) has been shown to reduce the PMP22 transcript and protein level. Here we present genomic and functional evidence, for the first time in a human CNV-associated phenotype, of the 3′ untranslated region (3′-UTR)-mediated role of microRNA repression on gene expression. The proband of the family presented with an early-onset, severe sensorimotor demyelinating neuropathy and harboured a novel de novo deletion in the PMP22 3′-UTR. The deletion is predicted to include the miR-29a seed binding site and transcript analysis of dermal myelinated nerve fibres using a novel platform, revealed a marked increase in PMP22 transcript levels. Functional evidence from Schwann cell lines harbouring the wildtype and mutant 3′-UTR showed significantly increased reporter assay activity in the latter which was not ameliorated by overexpression of a miR-29a mimic. This shows the importance of miR-29a in regulating PMP22 expression and opens an avenue for therapeutic drug development.
PMID:37337674 | DOI:10.1093/brain/awad203
SOURCE:
Brain : a journal of neurology
TAGS:
miR29a
CATEGORY:
Research
SUBCATEGORY:
n/a
DATE – PUBLISHED:
2023-06-20T06:54:32Z
DATE – DOI: 2023-06-20T06:54:32Z
DATE – PUBMED: 2023 Jun 20
DATE OUTPUT MATCHED: True
DATE – ADDED:
Tue, 20 Jun 2023 06:00:00 -0400
DATE – RETRIEVED:
06/20/23 06:38AM
2023-06-20T06:38:45-04:00
FEATURED IMAGE:
Media Uploaded (image/png)
IDENTIFIER:
pmid:37337674,doi:10.1093/brain/awad203
PUBMED ID:
pubmed:37337674
DOI:
10.1093/brain/awad203
LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/37337674/
LINK – DOI:
https://doi.org/10.1093/brain/awad203
LINK – PUBLISHER:
https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awad203/7202422
REFERENCES:
CMT Treatment Report, Urgent Research, 2023-06-20T06:38:45-04:00, https://www.cmttreatmentreport.com.