PRIM1 deficiency causes a distinctive primordial dwarfism syndrome

Genes Dev. 2020 Nov 1;34(21-22):1520-1533. doi: 10.1101/gad.340190.120.

David A Parry ^# ¹, Lukas Tamayo-Orrego ^# ¹, Paula Carroll ¹, Joseph A Marsh ¹, Philip Greene ¹, Olga Murina ¹, Carolina Uggenti ², Andrea Leitch ¹, Scottish Genomes Partnership, Rita Káposzta ³, Gabriella Merő ³, Andrea Nagy ³, Brigitta Orlik ⁴, Balázs Kovács-Pászthy ³, Alan J Quigley ⁵, Magdolna Riszter ³, Julia Rankin ⁶, Martin A M Reijns ¹, Katalin Szakszon ³, Andrew P Jackson ¹, Members of the Scottish Genome Partnership include

Affiliations

1 MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, the University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
2 Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, the University of Edinburgh, Edinburgh EH4 2XU, United Kingdom.
3 Institute of Pediatrics, Faculty of Medicine, University of Debrecen, Debrecen H-4032, Hungary.
4 Institute of Pathology, Faculty of Medicine, University of Debrecen, Debrecen H-4032, Hungary.
5 Department of Radiology, Royal Hospital for Sick Children, Edinburgh EH9 1LF, United Kingdom.
6 Department Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter EX1 2ED, United Kingdom.
# Contributed equally.

PMID: 33060134 DOI: 10.1101/gad.340190.120

Abstract

DNA replication is fundamental for cell proliferation in all organisms. Nonetheless, components of the replisome have been implicated in human disease, and here we report PRIM1 encoding the catalytic subunit of DNA primase as a novel disease gene. Using a variant classification agnostic approach, biallelic mutations in PRIM1 were identified in five individuals. PRIM1 protein levels were markedly reduced in patient cells, accompanied by replication fork asymmetry, increased interorigin distances, replication stress, and prolonged S-phase duration. Consequently, cell proliferation was markedly impaired, explaining the patients' extreme growth failure. Notably, phenotypic features distinct from those previously reported with DNA Polymerase genes were evident, highlighting differing developmental requirements for this core replisome component that warrant future investigation.

Keywords

DNA replication; genome stability; growth disorders; human genetics; rare disease.

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