Format

Send to

Choose Destination
Nat Genet. 2013 Aug;45(8):947-50. doi: 10.1038/ng.2670. Epub 2013 Jun 16.

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

Author information

1
Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.

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.

PMID:
23770608
PMCID:
PMC3785143
DOI:
10.1038/ng.2670
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center