POLR3A mutations cause nucleolus abnormalities and aberrant telomerase RNA metabolism in induced pluripotent stem cells from Wiedemann-Rautenstrauch premature aging syndrome patient.

Induced pluripotent stem cells (iPSCs) derived from patients with premature aging disorders are widely regarded as a foundation for both the study of fundamental aging mechanisms and preclinical testing of anti-aging therapies. The most well-studied is Hutchinson-Gilford progeria syndrome (HGPS), which is caused by a lamin A gene mutation. Comparing the progeroid phenotype in cell models of distinct premature aging syndromes is critical for identifying early and common aging hallmarks. In this study, using a non-integrative episomal approach we reprogrammed iPSCs from cells of a patient suffering from Wiedemann-Rautenstrauch Syndrome (WRS), which is caused by bi-allelic pathogenic mutations of the RNA polymerase III subunit A gene (POLR3A). In parallel, an iPSC line with the classic HGPS caused by a lamin A mutation was obtained. HGPS and WRS patient fibroblasts showed similar signs of cellular aging; however, unlike HGPS, the causal link between the premature aging phenotype and WRS driving mutations is unclear. RNA polymerase III is required for the transcription of small nuclear RNAs and being a target of TORC1 (Target of Rapamycin kinase Complex 1), it plays a role in longevity and aging in model organisms. Whereas lamin A is downregulated in iPSCs, allowing for regeneration of HGPS iPSCs, we found that POLR3A is upregulated during reprogramming. Enhanced expression of mutant POLR3A in WRS iPSCs led to nucleolus abnormalities and telomerase RNA component (TERC) sequestration in the nucleoli in WRS iPSCs. WRS iPSCs may be an important model for developing new therapeutic approaches affecting premature aging of stem cells.