dc.contributor.author | Weedon, MN | |
dc.contributor.author | Ellard, S | |
dc.contributor.author | Prindle, MJ | |
dc.contributor.author | Caswell, R | |
dc.contributor.author | Lango Allen, H | |
dc.contributor.author | Oram, R | |
dc.contributor.author | Godbole, K | |
dc.contributor.author | Yajnik, CS | |
dc.contributor.author | Sbraccia, P | |
dc.contributor.author | Novelli, G | |
dc.contributor.author | Turnpenny, P | |
dc.contributor.author | McCann, E | |
dc.contributor.author | Goh, KJ | |
dc.contributor.author | Wang, Y | |
dc.contributor.author | Fulford, J | |
dc.contributor.author | McCulloch, LJ | |
dc.contributor.author | Savage, DB | |
dc.contributor.author | O'Rahilly, S | |
dc.contributor.author | Kos, K | |
dc.contributor.author | Loeb, LA | |
dc.contributor.author | Semple, RK | |
dc.contributor.author | Hattersley, AT | |
dc.date.accessioned | 2017-03-13T11:11:01Z | |
dc.date.issued | 2013-08 | |
dc.description.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. | en_GB |
dc.description.sponsorship | This work was supported by NIHR Exeter Clinical Research Facility through funding for SE and ATH and general
infrastructure. The authors thank Michael Day, Annet Damhuis and Richard Gilbert for technical assistance. We
thank Karen Knapp for providing the data for the DEXA calculations. SE, ATH, SO are supported by Wellcome
Weedon et al. Page 6
Nat Genet. Author manuscript; available in PMC 2014 February 01.
Europe PMC Funders Author Manuscripts Europe PMC Funders Author Manuscripts
Trust Senior Investigator awards. DS and RKS (098498/Z/12/Z) are supported by Wellcome Trust Senior Research
Fellowships in Clinical Science. MNW is supported by the Wellcome Trust as part of the WT Biomedical
Informatics Hub funding. RO is supported by Diabetes UK. DS, RKS and SO are supported by the UK National
Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. KJG is supported by the Agency for
Science, Technology and Research, Singapore (A*STAR). LAL and MJP are supported by grants NCI-61-6845 and
62-4860. | en_GB |
dc.identifier.citation | Vol. 45, pp. 947 - 950 | en_GB |
dc.identifier.doi | 10.1038/ng.2670 | |
dc.identifier.uri | http://hdl.handle.net/10871/26501 | |
dc.language.iso | en | en_GB |
dc.publisher | Nature Publishing Group | en_GB |
dc.relation.url | https://www.ncbi.nlm.nih.gov/pubmed/23770608 | en_GB |
dc.subject | Abnormalities, Multiple | en_GB |
dc.subject | Animals | en_GB |
dc.subject | Catalytic Domain | en_GB |
dc.subject | Cell Line | en_GB |
dc.subject | DNA Polymerase III | en_GB |
dc.subject | Enzyme Activation | en_GB |
dc.subject | Facies | en_GB |
dc.subject | Fibrosis | en_GB |
dc.subject | Humans | en_GB |
dc.subject | Lipodystrophy | en_GB |
dc.subject | Magnetic Resonance Imaging | en_GB |
dc.subject | Male | en_GB |
dc.subject | Mice | en_GB |
dc.subject | Models, Molecular | en_GB |
dc.subject | Phenotype | en_GB |
dc.subject | Protein Conformation | en_GB |
dc.subject | Reading Frames | en_GB |
dc.subject | Sequence Deletion | en_GB |
dc.subject | Subcutaneous Fat, Abdominal | en_GB |
dc.subject | Syndrome | en_GB |
dc.title | An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy | en_GB |
dc.type | Article | en_GB |
dc.date.available | 2017-03-13T11:11:01Z | |
exeter.place-of-publication | United States | en_GB |
dc.description | This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record. | en_GB |
dc.identifier.journal | Nature Genetics | en_GB |
dc.identifier.pmcid | PMC3785143 | |
dc.identifier.pmid | 23770608 | |