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Pathogenic POLRMT variants in mice impair mtDNA transcription and affect perinatal survival

ABSTRACT: Mitochondrial gene expression is essential for oxidative phosphorylation (OXPHOS) that generates the bulk of the cellular ATP, and dysfunctional mitochondria is a common cause of human metabolic diseases. Recently, the first pathogenic variants in the only known mitochondrial RNA polymerase (POLRMT) were described. Patients present with a wide variety of clinical manifestations, such as hypotonia, short stature and developmental delay. Here, we modeled two human pathogenic POLRMT variants by creating the corresponding substitutions in mice: the dominant S582F and the recessive R984C variant. Mice homozygous for the R984C variant showed perinatal lethality without apparent embryonic developmental defects, thus showing that POLRMT has a critical role in the transition to oxidative metabolism at birth. Mice carrying the S582F variant were viable and exhibited decreased mitochondrial transcript levels due to impaired de novo transcription. However, mtDNA levels and in organello mtDNA replication remained normal, which recapitulates the molecular phenotypes observed in the patients. Altogether, our findings indicate that the conserved arginine near the active site is essential for POLRMT function, while the serine in the intercalating hairpin of the N-terminal domain is required for transcription but not primase activity. This study highlights genotype–phenotype differences and provides new insights into POLRMT function.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart, Liver

SUBMITTER: Akos Vegvari

LAB HEAD: Akos Vegvari

PROVIDER: PXD074595 | Pride | 2026-05-13

REPOSITORIES: Pride

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			Action	DRS
	20251216_AV_David_H01_2025-12-17_12310.d.zip	Other
	Heart_report.pg_matrix.tsv	Tabular
	Liver_report.pg_matrix.tsv	Tabular
	checksum.txt	Txt

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