Novel biallelic mutations in POLR1A: expansion of the phenotype and insight into the molecular mechanism

ABSTRACT: The eukaryotic genome is transcribed by three RNA polymerases (Pol) I, II and III; each transcribing different classes of RNAs. Pol I transcribes ribosomal DNA and produces the polycistronic rRNA 47S, which releases 28S, 18S and 5.8S rRNAs. Heterozygous mutations in the Pol I subunit POLR1A have been described in three patients presenting with Acrofacial Dysostosis, Cincinnati Type (MIM 616462), while a homozygous mutation in POLR1A was identified in two siblings, presenting developmental regression and several brain anomalies. We present three patients with homozygous mutations in POLR1A. Patient 1, a Norwegian male homozygous for POLR1A p.T642N, presented severe neurodegeneration with epilepsy, and died at 16 years of age. Patient 2, a 5.4-years-old Mexican male homozygous for POLR1A p.R667H, presented with severe neurodegeneration, epilepsy, and skeletal anomalies. Patient 3, a 2-year-old Dutch girl homozygous for POLR1A p.T642N, manifested severe global developmental delay, and brain anomalies. Structure superimposition of POLR1A wild-type and POLR1A T642N or R667H suggested a possible abnormal interaction between POLR1A and POLR2H. In vitro experiments showed that POLR1A T642N has higher transcriptional activity, abnormal rRNA processing, increased autophagy, deprotected telomeres, and reduced levels of p53. Proteomics analysis of patients 1 supported these findings, identifying dysfunction of pathways related to protein synthesis, ubiquitination, phagosome activities, and cell survival. In conclusion, we expand the phenotype of this rare disease and document a transcriptional defect affecting multiple processes, which impact cell survival.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Tuula Nyman  

LAB HEAD: Tuula Nyman

PROVIDER: PXD017431 | Pride | 2023-10-24

REPOSITORIES: pride