Investigation of a TRIM28 novel variant linked to intellectual disability
Abstract
TRIM28 is a developmental chromatin regulator. It influences pluripotency and preserves genomic integrity by suppressing transposable elements (TEs). A TRIM28 variant (T2123C) was recently identified in a pediatric patient with a neurodevelopmental disorder. Human induced pluripotent stem cells (iPSCs) harboring this variant were generated to investigate potential pathogenic outcomes. We found that the T2123C variant does not affect TRIM28 transcript or protein levels or its nuclear localization. However, the morphology of mutant cells appeared to be affected, and the compactness of colonies was reduced. Although expression of core pluripotency factors did not differ, transcriptome analysis unveiled alteration of neural development-related genes, suggesting priming of mutant iPSCs to a neural fate. Moreover, this mutation led to the de-repression of all TE families. Overall, this study revealed that the T2123C TRIM28 variant causes TE activation, dysregulation of iPSC morphology and premature expression of neural lineage genes without affecting core pluripotency factors.