An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy

Nat Genet. 2013 Aug;45(8):947-50. doi: 10.1038/ng.2670. Epub 2013 Jun 16.


DNA polymerase δ, whose catalytic subunit is encoded by POLD1, is responsible for lagging-strand DNA synthesis during DNA replication. It carries out this synthesis with high fidelity owing to its intrinsic 3'- to 5'-exonuclease activity, which confers proofreading ability. Missense mutations affecting the exonuclease domain of POLD1 have recently been shown to predispose to colorectal and endometrial cancers. Here we report a recurring heterozygous single-codon deletion in POLD1 affecting the polymerase active site that abolishes DNA polymerase activity but only mildly impairs 3'- to 5'-exonuclease activity. This mutation causes a distinct multisystem disorder that includes subcutaneous lipodystrophy, deafness, mandibular hypoplasia and hypogonadism in males. This discovery suggests that perturbing the function of the ubiquitously expressed POLD1 polymerase has unexpectedly tissue-specific effects in humans and argues for an important role for POLD1 function in adipose tissue homeostasis.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / diagnosis
  • Abnormalities, Multiple / genetics*
  • Animals
  • Catalytic Domain / genetics*
  • Cell Line
  • DNA Polymerase III / chemistry
  • DNA Polymerase III / genetics*
  • Enzyme Activation / genetics
  • Facies
  • Fibrosis
  • Humans
  • Lipodystrophy / complications
  • Lipodystrophy / genetics*
  • Magnetic Resonance Imaging
  • Male
  • Mice
  • Models, Molecular
  • Phenotype
  • Protein Conformation
  • Reading Frames*
  • Sequence Deletion*
  • Subcutaneous Fat, Abdominal / pathology
  • Syndrome


  • POLD1 protein, human
  • DNA Polymerase III

Associated data

  • PDB/3IAY
  • RefSeq/NM_002691