An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy.
Research paper by
Michael N MN Weedon, Sian S Ellard, Marc J MJ Prindle, Richard R Caswell, Hana H Lango Allen, Richard R Oram, Koumudi K Godbole, Chittaranjan S CS Yajnik, Paolo P Sbraccia, Giuseppe G Novelli, Peter P Turnpenny, Emma E McCann, Kim Jee KJ Goh, Yukai Y Wang, Jonathan J Fulford, Laura J LJ McCulloch, David B DB Savage, Stephen S O'Rahilly, Katarina K Kos, Lawrence A LA Loeb, Robert K RK Semple, Andrew T AT Hattersley
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.