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

Andrew Hattersley and colleagues show that an in-frame deletion in POLD1 affecting the polymerase active site causes a multisystem disorder characterized by lipodystrophy, deafness and mandibular hypoplasia. This recurrent mutation abolishes DNA polymerase activity but only mildly impairs 3'- to 5'-exonuclease activity. DNA polymerase δ, whose catalytic subunit is encoded by POLD1 , is responsible for lagging-strand DNA synthesis during DNA replication 1 . 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 2 . 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.