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Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy

A Corrigendum to this article was published on 01 July 2008

This article has been updated

Abstract

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.

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Figure 1: Clinical features of inbred families with PHO.
Figure 2: Localization of the PHO gene on chromosome 4q.
Figure 3: Characterization of the HPGD A140P mutant.
Figure 4: Abnormal prostaglandin metabolism in individuals with PHO.

Change history

  • 26 June 2008

    In the version of this article initially published, Figure 3a—d and Supplementary Figure 2a—c show 16-OH PGE2, not 15-OH PGE2. The errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

This study was supported by the UK Medical Research Council (Clinical Research Training Fellowship to S.U.) and Cancer Research UK.

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Authors

Contributions

S.U. and I.M.C. performed genetic mapping and mutation analysis. C.P.D. prepared and assayed recombinant HPGD and performed urine prostaglandin measurements. C.W.G.F. and S.E.V.P. performed structural analysis. S.U., M.A., G.H.I., P.S.H., A.L.-B. and C.P.B. identified subjects with PHO and performed clinical studies. A.F.M., C.P.B. and D.T.B. designed and supervised the project. D.T.B. wrote the manuscript.

Corresponding author

Correspondence to David T Bonthron.

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Supplementary Figures 1–3, Supplementary Tables 1–2 and Supplementary Note (PDF 6347 kb)

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Uppal, S., Diggle, C., Carr, I. et al. Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy. Nat Genet 40, 789–793 (2008). https://doi.org/10.1038/ng.153

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