PRIM1 Deficiency Causes a Distinctive Primordial Dwarfism Syndrome

David A. Parry, Lukas Tamayo Orrego, Paula Carroll, Joseph A Marsh, Philip Greene, Olga Murina, Carolina Uggenti, Andrea Leitch, The Scottish Genomes Partnership, Rita Káposzta, Gabriella Merő, Andrea Nagy, Brigitta Orlik, Balazs Kovács-Pászthy, Alan J Quigley, Magdolna Riszter, Julia Rankin, Martin A M Reijns, Katalin Szakszon, Andrew P Jackson

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.
Original languageEnglish
Pages (from-to)1520-1533
Number of pages14
JournalGenes & Development
Early online date15 Oct 2020
Publication statusPublished - 1 Nov 2020


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