Polymerase δ deficiency causes syndromic immunodeficiency with replicative stress

J Clin Invest. 2019 Oct 1;129(10):4194-4206. doi: 10.1172/JCI128903.


Polymerase δ is essential for eukaryotic genome duplication and synthesizes DNA at both the leading and lagging strands. The polymerase δ complex is a heterotetramer comprising the catalytic subunit POLD1 and the accessory subunits POLD2, POLD3, and POLD4. Beyond DNA replication, the polymerase δ complex has emerged as a central element in genome maintenance. The essentiality of polymerase δ has constrained the generation of polymerase δ-knockout cell lines or model organisms and, therefore, the understanding of the complexity of its activity and the function of its accessory subunits. To our knowledge, no germline biallelic mutations affecting this complex have been reported in humans. In patients from 2 independent pedigrees, we have identified what we believe to be a novel syndrome with reduced functionality of the polymerase δ complex caused by germline biallelic mutations in POLD1 or POLD2 as the underlying etiology of a previously unknown autosomal-recessive syndrome that combines replicative stress, neurodevelopmental abnormalities, and immunodeficiency. Patients' cells showed impaired cell-cycle progression and replication-associated DNA lesions that were reversible upon overexpression of polymerase δ. The mutations affected the stability and interactions within the polymerase δ complex or its intrinsic polymerase activity. We believe our discovery of human polymerase δ deficiency identifies the central role of this complex in the prevention of replication-related DNA lesions, with particular relevance to adaptive immunity.

Keywords: Adaptive immunity; DNA repair; Genetic diseases; Genetics; Immunology.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Alleles
  • Amino Acid Substitution
  • DNA Polymerase III / chemistry
  • DNA Polymerase III / deficiency*
  • DNA Polymerase III / genetics*
  • DNA Replication / genetics
  • Enzyme Stability / genetics
  • Genes, Recessive
  • Germ-Line Mutation*
  • Humans
  • Immunologic Deficiency Syndromes / enzymology*
  • Immunologic Deficiency Syndromes / genetics*
  • Male
  • Models, Molecular
  • Multienzyme Complexes / chemistry
  • Multienzyme Complexes / deficiency
  • Multienzyme Complexes / genetics
  • Mutation, Missense
  • Neurodevelopmental Disorders / enzymology
  • Neurodevelopmental Disorders / genetics
  • Pedigree
  • Protein Conformation
  • Protein Interaction Domains and Motifs
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Young Adult


  • Multienzyme Complexes
  • Recombinant Proteins
  • POLD1 protein, human
  • POLD2 protein, human
  • DNA Polymerase III