title: An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy.
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.
authors.affiliation: Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Weedon
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Prindle
authors.forename: Richard
authors.initials: R
authors.lastname: Caswell
authors.forename: Hana
authors.initials: H
authors.lastname: Lango Allen
authors.forename: Richard
authors.initials: R
authors.lastname: Oram
authors.forename: Koumudi
authors.initials: K
authors.lastname: Godbole
authors.forename: Chittaranjan S
authors.initials: CS
authors.lastname: Yajnik
authors.forename: Paolo
authors.initials: P
authors.lastname: Sbraccia
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Novelli
authors.forename: Peter
authors.initials: P
authors.lastname: Turnpenny
authors.forename: Emma
authors.initials: E
authors.lastname: McCann
authors.forename: Kim Jee
authors.initials: KJ
authors.lastname: Goh
authors.forename: Yukai
authors.initials: Y
authors.lastname: Wang
authors.forename: Jonathan
authors.initials: J
authors.lastname: Fulford
authors.forename: Laura J
authors.initials: LJ
authors.lastname: McCulloch
authors.forename: David B
authors.initials: DB
authors.lastname: Savage
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: Katarina
authors.initials: K
authors.lastname: Kos
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Loeb
authors.forename: Robert K
authors.initials: RK
authors.lastname: Semple
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics*; D000818:Animals; D020134:Catalytic Domain / Q000235:genetics*; D002460:Cell Line; D004258:DNA Polymerase III / Q000737:chemistry / Q000235:genetics*; D004789:Enzyme Activation / Q000235:genetics; D019066:Facies; D005355:Fibrosis; D006801:Humans; D008060:Lipodystrophy / Q000150:complications / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008958:Models, Molecular; D010641:Phenotype; D011487:Protein Conformation; D016364:Reading Frames; D017384:Sequence Deletion; D050507:Subcutaneous Fat, Abdominal / Q000473:pathology; D013577:Syndrome
chemical_list: C434055:POLD1 protein, human; D004258:DNA Polymerase III