An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy
Weedon, MN; Ellard, S; Prindle, MJ; et al.Caswell, R; Lango Allen, H; Oram, R; Godbole, K; Yajnik, CS; Sbraccia, P; Novelli, G; Turnpenny, P; McCann, E; Goh, KJ; Wang, Y; Fulford, J; McCulloch, LJ; Savage, DB; O'Rahilly, S; Kos, K; Loeb, LA; Semple, RK; Hattersley, AT
Date: 1 August 2013
Article
Journal
Nature Genetics
Publisher
Nature Publishing Group
Publisher DOI
Related links
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 ...
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.
Institute of Biomedical & Clinical Science
Collections of Former Colleges
Item views 0
Full item downloads 0