title: Prostaglandin transporter mutations cause pachydermoperiostosis with myelofibrosis.
abstract: Pachydermoperiostosis, or primary hypertrophic osteoarthropathy (PHO), is an inherited multisystem disorder, whose features closely mimic the reactive osteoarthropathy that commonly accompanies neoplastic and inflammatory pathologies. We previously described deficiency of the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (HPGD) as a cause of this condition, implicating elevated circulating prostaglandin E(2) (PGE(2)) as causative of PHO, and perhaps also as the principal mediator of secondary HO. However, PHO is genetically heterogeneous. Here, we use whole-exome sequencing to identify recessive mutations of the prostaglandin transporter SLCO2A1, in individuals lacking HPGD mutations. We performed exome sequencing of four probands with severe PHO, followed by conventional mutation analysis of SLCO2A1 in nine others. Biallelic SLCO2A1 mutations were identified in 12 of the 13 families. Affected individuals had elevated urinary PGE(2), but unlike HPGD-deficient patients, also excreted considerable quantities of the PGE(2) metabolite, PGE-M. Clinical differences between the two groups were also identified, notably that SLCO2A1-deficient individuals have a high frequency of severe anemia due to myelofibrosis. These findings reinforce the key role of systemic or local prostaglandin excess as the stimulus to HO. They also suggest that the induction or maintenance of hematopoietic stem cells by prostaglandin may depend upon transporter activity.
authors.affiliation: School of Medicine, University of Leeds, Leeds, United Kingdom.
authors.forename: Christine P
authors.initials: CP
authors.lastname: Diggle
authors.forename: David A
authors.initials: DA
authors.lastname: Parry
authors.forename: Clare V
authors.initials: CV
authors.lastname: Logan
authors.forename: Paul
authors.initials: P
authors.lastname: Laissue
authors.forename: Carolina
authors.initials: C
authors.lastname: Rivera
authors.forename: Carlos Martín
authors.initials: CM
authors.lastname: Restrepo
authors.forename: Dora J
authors.initials: DJ
authors.lastname: Fonseca
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Morgan
authors.forename: Yannick
authors.initials: Y
authors.lastname: Allanore
authors.forename: Michaela
authors.initials: M
authors.lastname: Fontenay
authors.forename: Julien
authors.initials: J
authors.lastname: Wipff
authors.forename: Mathilde
authors.initials: M
authors.lastname: Varret
authors.forename: Laure
authors.initials: L
authors.lastname: Gibault
authors.forename: Nadezhda
authors.initials: N
authors.lastname: Dalantaeva
authors.forename: Márta
authors.initials: M
authors.lastname: Korbonits
authors.forename: Bowen
authors.initials: B
authors.lastname: Zhou
authors.forename: Gang
authors.initials: G
authors.lastname: Yuan
authors.forename: Ghita
authors.initials: G
authors.lastname: Harifi
authors.forename: Kivanc
authors.initials: K
authors.lastname: Cefle
authors.forename: Sukru
authors.initials: S
authors.lastname: Palanduz
authors.forename: Hadim
authors.initials: H
authors.lastname: Akoglu
authors.forename: Petra J
authors.initials: PJ
authors.lastname: Zwijnenburg
authors.forename: Klaske D
authors.initials: KD
authors.lastname: Lichtenbelt
authors.forename: Bérengère
authors.initials: B
authors.lastname: Aubry-Rozier
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.forename: Maria
authors.initials: M
authors.lastname: Accadia
authors.forename: Francesco
authors.initials: F
authors.lastname: Brancati
authors.forename: Eamonn G
authors.initials: EG
authors.lastname: Sheridan
authors.forename: Graham R
authors.initials: GR
authors.lastname: Taylor
authors.forename: Ian M
authors.initials: IM
authors.lastname: Carr
authors.forename: Colin A
authors.initials: CA
authors.lastname: Johnson
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Markham
authors.forename: David T
authors.initials: DT
authors.lastname: Bonthron
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D009154:Mutation; D027361:Organic Anion Transporters / Q000235:genetics*; D010004:Osteoarthropathy, Primary Hypertrophic / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism; D055728:Primary Myelofibrosis / Q000235:genetics*; D011453:Prostaglandins / Q000378:metabolism; D055815:Young Adult
chemical_list: D027361:Organic Anion Transporters; D011453:Prostaglandins; C503526:SLCO2A1 protein, human