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



DNA polymerase δ, whose catalytic subunit is encoded by POLD1, is responsible for lagging-strand DNA synthesis during DNA replication1. 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 cancers2. 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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Figure 1: Clinical characteristics of individuals with MDP syndrome.
Figure 2: Protein schematic and modeling of POLD1 alterations.
Figure 3: Polymerase δ with Ser605del mutant POLD1 has no detectable polymerase activity but has robust exonuclease activity.

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We thank M. Day, A. Damhuis and R. Gilbert for technical assistance. We thank K. Knapp for providing the data for the DEXA calculations. We thank L. Tung (University of Cambridge) for providing the human tissue whole-RNA panel. This work was supported by the NIHR Exeter Clinical Research Facility through funding for S.E. and A.T.H., and general infrastructure. S.E., A.T.H. and S.O. are supported by Wellcome Trust Senior Investigator awards 098395/Z/12/A and 098395/Z/12/Z. D.B.S. and R.K.S. are supported by Wellcome Trust Senior Research Fellowships in Clinical Science (098498/Z/12/Z). M.N.W. is supported by the Wellcome Trust as part of Wellcome Trust Biomedical Informatics Hub funding. R.O. is supported by Diabetes UK. D.B.S., R.K.S. and S.O. are supported by the UK NIHR Cambridge Biomedical Research Centre. K.J.G. is supported by the Agency for Science, Technology and Research, Singapore (A*STAR). Research reported in this publication by M.J.P. and L.A.L. was supported by the National Cancer Institute of the US National Institutes of Health under awards R01CA102029 and P01CA077852. The opinions in this paper are soley those of the authors and do not necessarily represent the views of the US National Institutes of Health, the Department of Health (England) or other funders.

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S.E. and A.T.H. designed the study. M.N.W. and H.L.A. performed bioinformatics analyses. R.C. performed the exome sequencing and structural modeling. M.J.P., K.J.G., Y.W., J.F., L.J.M., L.A.L., K.K. and R.K.S. performed the functional studies. R.C. and S.E. performed the Sanger sequencing analysis and interpreted the results. R.O., K.G., C.S.Y., P.S., G.N., P.T., E.M., D.B.S., S.O., R.K.S. and A.T.H. analyzed the clinical data. M.N.W., S.E., M.J.P., R.K.S. and A.T.H. prepared the draft manuscript. All authors contributed to discussion of the results and manuscript preparation.

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Correspondence to Andrew T Hattersley.

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Weedon, M., Ellard, S., Prindle, M. et al. An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy. Nat Genet 45, 947–950 (2013).

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