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A Study of PSTPIP2, NOD2, and LPIN2 Genes MARGARITA HURTADO-NEDELEC, SYLVIE CHOLLET-MARTIN, DIANA CHAPETON, JEAN-PIERRE HUGOT, GILLES HAYEM, and BÉNÉDICTE GÉRARD

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A Study of PSTPIP2, NOD2, and LPIN2 Genes MARGARITA HURTADO-NEDELEC, SYLVIE CHOLLET-MARTIN, DIANA CHAPETON, JEAN-PIERRE HUGOT, GILLES HAYEM, and BÉNÉDICTE GÉRARD Genetic Susceptibility Factors in a Cohort of 38 Patients with SAPHO Syndrome: A Study of PSTPIP2, NOD2, and LPIN2 Genes MARGARITA HURTADO-NEDELEC, SYLVIE CHOLLET-MARTIN, DIANA CHAPETON, JEAN-PIERRE HUGOT, GILLES HAYEM, and BÉNÉDICTE GÉRARD ABSTRACT. Objective. The SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis) is a rare disorder that mainly affects bone and skin. Chronic multifocal osteitis is the main diagnostic feature. Genetic studies of HLA genes have shown no role for these class II antigens, whereas studies of 2 mouse models (cmo and Lupo) point to a role of the PSTPIP2 gene. We analyzed the PSTPIP2 gene in patients with SAPHO syndrome. Methods. In a cohort of 38 patients with SAPHO we analyzed PSTPIP2 and 2 other candidate genes, NOD2/CARD15 (Crohn’s disease occurs in about 10% of SAPHO patients), and LPIN2 (clinical similarities of SAPHO with Majeed syndrome). Results. Rare variants of the 3 genes observed in patients with SAPHO were not specific or were not found more frequently compared to controls, suggesting no major pathogenetic role of these genes in the SAPHO syndrome. Conclusion. We found no association between PSTPIP2, NOD2, and LPIN2 variants and the SAPHO syndrome. (First Release Dec 23 2009; J Rheumatol 2010;37:401–9; doi:10.3899/jrheum.090456) Key Indexing Terms: SAPHO SYNDROME GENE POLYMORPHISM PSTPIP2 POLYMORPHONUCLEAR NEUTROPHILS NOD2 LPIN2 The SAPHO syndrome (synovitis, acne, pustulosis, hyper- immune responses, but the etiopathogenesis is still largely ostosis, and osteitis) is a rare disorder that mainly affects unknown. Despite the pathological characteristics that the bone and skin, with multifocal osteitis as the main diagnos- SAPHO syndrome shares with some spondyloarthropathies, tic feature. The broad spectrum of clinical features in the such as axial skeleton involvement, skin lesions, and inflam- SAPHO syndrome, and their highly varied combinations, matory bowel disease (IBD)9-11, some authors underline the raise diagnostic difficulties, especially in patients with only absence of certain typical features of spondyloarthropathies, bone lesions1-3. This results in a probable underestimation such as a strong association with HLA-B27, familial segre- of the frequency of the disease. Several factors have been gation, male predominance, and typical radiographic implicated in the development of the SAPHO syndrome, lesions12. such as Propionibacterium acnes infection4-8 and impaired We recently reported strong humoral and cellular proinflammatory responses in a group of 29 patients with From the Unité d’Immunologie Auto-immunité et Hypersensibilités, SAPHO syndrome, as shown by high interleukin 8 (IL-8) AP-HP, Hôpital Bichat-Claude Bernard; Universite Paris-Sud 11, and IL-18 plasma levels and hyperproduction of the 2 INSERM, IFR 141, UMR756 Châtenay-Malabry; AP-HP, INSERM; cytokines by purified polymorphonuclear neutrophils Université Paris Diderot; Hôpital Robert-Debré, Service de Gastro-entérologie; AP-HP, Hôpital Bichat-Claude Bernard, Service de (PMN) ex vivo. P. acnes-specific PMN deactivation was 11 Rhumatologie; and AP-HP, Hôpital Robert-Debré, Service de Génétique, also observed α. We and others have found that anti-tumor Paris, France. necrosis factor- therapies (infliximab and etanercept) can M. Hurtado-Nedelec, MD, PhD; S. Chollet-Martin, PharmD, PhD, be beneficial in patients with refractory SAPHO AP-HP, Hôpital Bichat-Claude Bernard, Unité d’Immunologie 11,13-16 Auto-immunité et Hypersensibilités, and Universite Paris-Sud 11, syndrome . INSERM; D. Chapeton, PhD, AP-HP, Hôpital Bichat-Claude Bernard, Genetic factors have been implicated in SAPHO syn- Unité d’Immunologie Auto-immunité et Hypersensibilités; J-P. Hugot, 17-19 MD, PhD, AP-HP, Hôpital Robert-Debré, Service de Génétique; drome, based on familial clustering . However, genetic G. Hayem, MD, PhD, AP-HP, Hôpital Bichat-Claude Bernard, Service de studies of class II HLA antigens revealed no role for Rhumatologie; B. Gérard, PharmD, PhD, AP-HP, Hôpital Robert-Debré, HLA-B27, HLA-Cw6, or HLA-DR9,10,20. Service de Génétique. The recent description of mutated genes in 2 mouse mod- Address correspondence to Dr. B. Gérard, Service de Génétique, 21 Hôpital Robert Debré, 75018 Paris, France. els, cmo (chronic multifocal osteomyelitis, p.Leu98Pro) E-mail: [email protected] and Lupo (macrophage infiltration, paw osteolysis, and ear 22 Accepted for publication August 24, 2009. necrosis, p.Ile282Asn) , that share some manifestations Personal non-commercial use only. The Journal of Rheumatology Copyright © 2010. All rights reserved. Hurtado-Nedelec: Genetic factors in SAPHO 401 Downloaded on October 1, 2021 from www.jrheum.org with the human SAPHO syndrome has provided new informed of the purpose of the study and gave their written informed con- insights into the molecular basis of the SAPHO syndrome. sent. All the procedures were conducted in accord with our institutional eth- ical guidelines. These 2 models involve nonsynonymous homozygous As a control group, 162 unaffected and unrelated west European mutations in the proline serine threonine phosphatase inter- Caucasians were screened for the polymorphisms found in the patients. acting protein 2 gene (pstpip2). Moreover, low levels of pst- These subjects were recruited from CEPH (Centre d’Étude du pip2 have been linked to abnormal macrophage functions, Polymorphisme Humain), which maintains a database for genetic markers suggesting that pstpip2 mutations might be related to the that have been typed in the CEPH reference family resource for linkage mapping37,38. bone destruction and skin inflammation observed in cmo 22,23 Genetic analysis. Genomic DNA was isolated from peripheral blood leuko- and Lupo mice . cytes by using the QIAamp DNA Blood Midi kit (QIAGEN GmbH, Hilden, SAPHO-related human diseases point to other possible Germany) following manufacturer’s recommendations. candidate genes. Majeed syndrome is an autoinflammatory Coding sequences and intron-exon junctions of PSTPIP2 (GenBank bone disease that shares with SAPHO syndrome features of NM_024430), LPIN2 (GenBank NM_014646), and NOD2 (GenBank chronic recurrent multifocal osteitis and inflammatory der- AF_178930) were direct sequenced. Polymerase chain reaction (PCR) and sequencing conditions for PST- matosis23,24. Recently, LPIN2 mutations have been impli- 25,26 PIP2, NOD2, and LPIN2 are available on request. Primers are described in cated in this disease ; lipin 2 catalyzes the transformation Table 1. Purified PCR amplification products were sequenced using the of phosphatidic acid (PA) into diacylglycerol. As the intra- BigDye Terminator Cycle Sequencing Kit v.1.1 (Applied Biosystems, cellular PA concentration regulates the mTOR (mammalian Foster City, CA, USA) according to manufacturer’s instructions, and were target of rapamycin), cell cycle, and RANKL (receptor acti- resolved on an ABI 3100 automated sequencer (Applied Biosystems). κ 27 Sequence data were aligned with SeqScape 2.0 software and compared to vator of nuclear factor- B) pathway , a lipin 2 abnormality the published sequences of PSTPIP2, LPIN2, and NOD2. might account for the altered bone proliferation observed in Statistical analysis. Chi-square test was used for case-control association Majeed syndrome. analysis. The Mann-Whitney test and ANOVA, respectively, were used to Because of the high prevalence (10%) of chronic IBD in compare qualitative and quantitative variables between groups. The thresh- patients with SAPHO10,28-30 we also studied the main gene old of statistical significance was set at p < 0.05. Correlations between clin- involved in Crohn’s disease (CD), NOD2/CARD15. NOD2 ical or biological variables and presence of one or several variants were sought using the Spearman coefficient or Mann-Whitney test. is an intracellular receptor of muramyl dipeptide (MDP), which is the minimal common component in the peptido- RESULTS glycans of Gram-negative and Gram-positive bacteria; this Clinical description of patients. We investigated 38 patients molecule is thus thought to serve as a general sign of bacte- rial infection31,32. NOD2 gene mutations lead to intestinal (30 female, 8 male) with SAPHO syndrome. The syndrome tolerance breakdown, and this might result in increased was sporadic in 34 cases and familial in 4 cases (2 families). microbial translocation and a strong inflammatory response Mean age at onset was 31.3 ± 2.3 years (range 12–65). in the gut of patients with IBD33,34. Interestingly, in vitro Osteitis was unifocal in 17 patients (44.7%) and multifocal studies have shown that NOD2-activating agonists can in 21 patients (55.26%). The mean number ± SEM of bone induce IL-8 production by monocytes and dendritic cells35. lesions was 1.9 ± 0.3 (range 1–8), and the mean number of We investigated whether SAPHO syndrome is associated involved joints [anterior chest wall (ACW), pelvis, or distal with PSTPIP2, LPIN2, or NOD2 polymorphism in 38 joints] was 1.9 ± 0.3 (range 1–5). Skin lesions were present French patients. in 34 (89%) patients and consisted of palmoplantar pustulo- sis in 19 cases (50%), severe acne in 8 cases (21%), and pso- MATERIALS AND METHODS riasis vulgaris in 20 cases (52.6%). Thirteen patients (34%) Patients and phenotyping. The study population consisted of consecutive had 2 concomitant skin lesions (Appendix 1). No patient had patients attending the Rheumatology Department, Bichat teaching hospital, detectable rheumatoid factor, anti-citrullinated cyclic pep- Paris, France. We studied
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