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Journal article
Functional characterization of the MED12 p.Arg1138Trp variant in females: implications for neural development and disease mechanism
Molecular medicine (Cambridge, Mass.), Vol.31(1), 300
2025
PMID: 41023835
Abstract
Background
Seven female individuals with multiple congenital anomalies, developmental delay and/or intellectual disability have been found to have a genetic variant of uncertain significance in the mediator complex subunit 12 gene (MED12 c.3412C>T, p.Arg1138Trp). The functional consequence of this genetic variant in disease is undetermined, and insight into disease mechanism is required.
Methods
We identified a de novo MED12 p.Arg1138Trp variant in a female patient and compared disease phenotypes with six female individuals identified in the literature. To investigate affected biological pathways, we derived two induced pluripotent stem cell (iPSC) lines from the patient: one expressing wildtype MED12 and the other expressing the MED12 p.Arg1138Trp variant. We performed neural disease modelling, transcriptomics and protein analysis, comparing healthy and variant cells.
Results
When comparing the two cell lines, we identified altered gene expression in neural cells expressing the variant, including genes regulating RNA polymerase II activity, transcription, pre-mRNA processing, and neural development. We also noted a decrease in MED12L expression. Pathway analysis indicated temporal delays in axon development, forebrain differentiation, and neural cell specification with significant upregulation of pre-ribosome complex gene pathways.
Conclusion
In a human neural model, expression of MED12 p.Arg1138Trp altered neural cell development and dysregulated the pre-ribosome complex providing functional evidence of disease aetiology and mechanism in MED12-related disorders.
Details
- Title
- Functional characterization of the MED12 p.Arg1138Trp variant in females: implications for neural development and disease mechanism
- Authors/Creators
- Nicole C Shaw - The University of Western AustraliaSaraya Harrison - Murdoch UniversityKevin Chen - The Kids Research Institute Australia, The University of Western Australia, Nedlands, WA, AustraliaCatherine A Forbes - The Kids Research Institute AustraliaEmma Kuzminski - The University of Western AustraliaMitchell Hedges - The University of Western AustraliaKathryn O Farley - The University of Western AustraliaMichelle Ward - King Edward Memorial HospitalLily Loughman - King Edward Memorial HospitalCathryn Poulton - King Edward Memorial HospitalGareth Baynam - King Edward Memorial HospitalTimo Lassmann - The Kids Research Institute AustraliaVanessa S Fear - The Kids Research Institute Australia
- Publication Details
- Molecular medicine (Cambridge, Mass.), Vol.31(1), 300
- Publisher
- BioMed Central Ltd unless otherwise stated. Part of Springer Nature.
- Identifiers
- 991005816848907891
- Copyright
- © The Author(s) 2025.
- Murdoch Affiliation
- School of Medical, Molecular and Forensic Sciences
- Language
- English
- Resource Type
- Journal article
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