PXD017431

PXD017431 is an original dataset announced via ProteomeXchange.

Title	Novel biallelic mutations in POLR1A: expansion of the phenotype and insight into the molecular mechanism
Description	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.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_09:06:24.554.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Tuula Nyman
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2020-02-07 06:13:34	ID requested
1	2023-10-24 08:45:44	announced
⏵ 2	2023-11-14 09:06:32	announced	2023-11-14: Updated project metadata.

Misceo D, Lirussi L, Str, ø, mme P, Sumathipala D, Guerin A, Wolf NI, Server A, Stensland M, Dalhus B, Tolun A, Kroes HY, Nyman TA, Nilsen HL, Frengen E, A homozygous POLR1A variant causes leukodystrophy and affects protein homeostasis. Brain, 146(8):3513-3527(2023) [pubmed]

submitter keyword: POLR1A, RNA Polymerase I, defective rRNA processing

neurodegenerative disease

seizures

childhood disease

Tuula Nyman
contact affiliation	Head of Proteomics
contact email	tuula.nyman@medisin.uio.no
lab head
Tuula Nyman
contact affiliation	University of Oslo
contact email	tuula.nyman@medisin.uio.no
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/10/PXD017431

PRIDE project URI

• PRIDE
  1. PXD017431
     1. Label: PRIDE project
     2. Name: Novel biallelic mutations in POLR1A: expansion of the phenotype and insight into the molecular mechanism