PXD074595-1

PXD074595 is an original dataset announced via ProteomeXchange.

Title	Pathogenic POLRMT variants in mice impair mtDNA transcription and affect perinatal survival
Description	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.
HostingRepository	PRIDE
AnnounceDate	2026-05-13
AnnouncementXML	Submission_2026-05-13_08:49:05.754.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Akos Vegvari
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	iodoacetamide derivatized residue
Instrument	timsTOF HT

Revision	Datetime	Status	ChangeLog Entry
0	2026-02-18 10:47:24	ID requested
⏵ 1	2026-05-13 08:49:06	announced

Dataset with its publication pending

submitter keyword: mouse models, mtDNA, mitochondria,POLRMT

Akos Vegvari
contact affiliation	Karolinska Institutet, Stockholm, Sweden
contact email	akos.vegvari@ki.se
lab head
Akos Vegvari
contact affiliation	Karolinska Institutet
contact email	akos.vegvari@ki.se
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD074595
     1. Label: PRIDE project
     2. Name: Pathogenic POLRMT variants in mice impair mtDNA transcription and affect perinatal survival