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

Michael N. Weedon, 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. LoebRobert K. Semple, Andrew T. Hattersley

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)947-950
Number of pages4
JournalNature Genetics
Issue number8
Publication statusPublished - Aug 2013

ASJC Scopus subject areas

  • Genetics


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