Details

Autor(en) / Beteiligte

• Weedon, Michael N
• Ellard, Sian
• Prindle, Marc J
• Caswell, Richard
• Lango Allen, Hana
• Oram, Richard
• Godbole, Koumudi
• Yajnik, Chittaranjan S
• Sbraccia, Paolo
• Novelli, Giuseppe
• Turnpenny, Peter
• McCann, Emma
• Goh, Kim Jee
• Wang, Yukai
• Fulford, Jonathan
• McCulloch, Laura J
• Savage, David B
• O'Rahilly, Stephen
• Kos, Katarina
• Loeb, Lawrence A
• Semple, Robert K
• Hattersley, Andrew T

Titel

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

Ist Teil von

• Nature genetics, 2013-08, Vol.45 (8), p.947-950

Ort / Verlag

United States

Erscheinungsjahr

2013

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.