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

Affiliation

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.

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