PRIM1 deficiency causes a distinctive primordial dwarfism syndrome

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

Research output: Contribution to journalArticlepeer-review


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
Issue number21-22
Publication statusPublished - 15 Oct 2020


  • DNA replication
  • genome stability
  • growth disorders
  • human genetics
  • rare disease


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