Letter abstract
Nature Genetics 40, 789 - 793 (2008)
Published online: 25 May 2008 | Corrected online: 26 June 2008 | doi:10.1038/ng.153
There is a Corrigendum (July 2008) associated with this Letter.
There is a Corrigendum (July 2008) associated with this Letter.
There is a Corrigendum (July 2008) associated with this Letter.
There is a Corrigendum (July 2008) associated with this Letter.
Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy
Sandeep Uppal1,2,
Christine P Diggle1,
Ian M Carr1,
Colin W G Fishwick3,
Mushtaq Ahmed4,
Gamal H Ibrahim5,
Philip S Helliwell1,
Anna Latos-Biele
ska6,
Simon E V Phillips7,
Alexander F Markham1,
Christopher P Bennett4
&
David T Bonthron1,4
Digital clubbing, recognized by Hippocrates in the fifth century BC, is the outward hallmark of pulmonary hypertrophic osteoarthropathy, a clinical constellation that develops secondary to various acquired diseases, especially intrathoracic neoplasm1. The pathogenesis of clubbing and hypertrophic osteoarthropathy has hitherto been poorly understood, but a clinically indistinguishable primary (idiopathic) form of hypertrophic osteoarthropathy (PHO) is recognized2, 3. This familial disorder can cause diagnostic confusion, as well as significant disability. By autozygosity methods, we mapped PHO to chromosome 4q33–q34 and identified mutations in HPGD, encoding 15-hydroxyprostaglandin dehydrogenase, the main enzyme of prostaglandin degradation. Homozygous individuals develop PHO secondary to chronically elevated prostaglandin E2 levels. Heterozygous relatives also show milder biochemical and clinical manifestations. These findings not only suggest therapies for PHO, but also imply that clubbing secondary to other pathologies may be prostaglandin mediated. Testing for HPGD mutations and biochemical testing for HPGD deficiency in patients with unexplained clubbing might help to obviate extensive searches for occult pathology.
- Leeds Institute of Molecular Medicine, University of Leeds, St. James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
- Department of Ear, Nose and Throat, York Hospital, Wigginton Road, York YO31 8HE, UK.
- School of Chemistry, University of Leeds, Leeds LS2 9JT, UK.
- Yorkshire Regional Genetics Service, St. James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
- Department of Rheumatology, St. Luke's Hospital, Little Horton Lane, Bradford BD5 0NA, UK.
-
Department of Medical Genetics, University of Medical Sciences, Grunwaldzka 55, pav.15, 60–352 Pozna, Poland.
- Astbury Centre for Structural Molecular Biology, Institute for Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, UK.
Correspondence to: David T Bonthron1,4 e-mail: d.t.bonthron@leeds.ac.uk
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