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.
Michael N Weedon  1 ,  Sian Ellard ,  Marc J Prindle ,  Richard Caswell ,  Hana Lango Allen ,  Richard Oram ,  Koumudi Godbole ,  Chittaranjan S Yajnik ,  Paolo Sbraccia ,  Giuseppe Novelli ,  Peter Turnpenny ,  Emma McCann ,  Kim Jee Goh ,  Yukai Wang ,  Jonathan Fulford ,  Laura J McCulloch ,  David B Savage ,  Stephen O'Rahilly ,  Katarina Kos ,  Lawrence A Loeb ,  Robert K Semple ,  Andrew T Hattersley
Affiliations
  • 1. Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
PMID: 23770608 DOI: 10.1038/ng.2670
Abstract

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.