Journal Article

Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy

Ahmed, Mushtaq, Bennett, Christopher P, Helliwell, Philip S, Phillips, Simon E V, Ibrahim, Gamal H, Latos-Bieleńska, Anna, Uppal, Sandeep, Diggle, Christine P, Carr, Ian M, Markham, Alexander F, Fishwick, Colin W G, Bonthron, David T

2008

Overview

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 neoplasm 1 . The pathogenesis of clubbing and hypertrophic osteoarthropathy has hitherto been poorly understood, but a clinically indistinguishable primary (idiopathic) form of hypertrophic osteoarthropathy (PHO) is recognized 2 , 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 E 2 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Adolescent / Adult / Agriculture / Amino Acid Sequence / Animal Genetics and Genomics / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Cancer Research / Child / Chromosomes, Human, Pair 4 - genetics / Complications and side effects / Consanguinity / Crystal structure / Dehydrogenase / Diagnosis / Dinoprostone - urine / Diseases of the osteoarticular system / Female / Frameshift Mutation - genetics / Fundamental and applied biological sciences. Psychology / Gene Function / Gene mutations / Genetic aspects / Genetics / Genetics of eukaryotes. Biological and molecular evolution / Genome, Human / Heterozygote / Homozygote / Human Genetics / Humans / Hydroxyprostaglandin Dehydrogenases - chemistry / Hydroxyprostaglandin Dehydrogenases - genetics / Hydroxyprostaglandin Dehydrogenases - metabolism / Identification and classification / Joint diseases / letter / Male / Malformations and congenital and or hereditary diseases involving bones. Joint deformations / Medical research / Medical sciences / Middle Aged / Models, Molecular / Molecular Sequence Data / Mutation / Osteoarthropathy, Primary Hypertrophic - enzymology / Osteoarthropathy, Primary Hypertrophic - etiology / Osteoarthropathy, Primary Hypertrophic - pathology / Oxidoreductases / Pathology / Pedigree / Physiological aspects / Primary hypertrophic osteoarthropathy / Protein Conformation / Proteins / Recombinant Proteins - genetics / Recombinant Proteins - isolation & purification / Recombinant Proteins - metabolism / Risk factors / Sequence Homology, Amino Acid