POLR1A, encoding the largest subunit of RNA Polymerase I, is crucial for ribosomal RNA (rRNA) transcription, a rate-limiting step in ribosome biogenesis [1,2,3,4]. Ribosome biogenesis is essential for cell survival and protein translation, and thus POLR1A is of great biological importance. Genetic models, such as mouse models, are valuable for studying its functions.

Heterozygous pathogenic variants in POLR1A cause acrofacial dysostosis, Cincinnati-type, with phenotypes including craniofacial anomalies, neurodevelopmental abnormalities, and structural cardiac defects [1]. Modeling allelic series of POLR1A variants in vitro and in vivo shows variable effects of pathogenic variants on rRNA synthesis and nucleolar morphology [1]. Conditional mutagenesis in mouse neural crest cells, the second heart field, and forebrain precursors reveals that loss of Polr1a in these lineages causes cell-autonomous apoptosis and embryonic malformations [1]. In a zebrafish model of Acrofacial Dysostosis-Cincinnati type, polr1a-/-mutants have deficient 47S rRNA transcription, reduced monosomes and polysomes, and protein translation defects, leading to Tp53-dependent neuroepithelial apoptosis, diminished neural crest cell proliferation, and cranioskeletal anomalies [3].

In conclusion, POLR1A is essential for rRNA transcription and ribosome biogenesis, which are crucial for cell proliferation and survival. Mouse and zebrafish models have revealed its role in craniofacial, neural, and cardiac development. Disruptions in POLR1A function can lead to ribosomopathies, highlighting its significance in understanding the pathogenesis of these congenital disorders [1,3,4].