A missense mutation in pstpip2 is associated with the murine autoinflammatory disorder chronic multifocal osteomyelitis

Abstract

Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory disorder that primarily affects bone but is often accompanied by inflammation of the skin and/or gastrointestinal tract. The etiology is unknown but evidence suggests a genetic component to disease susceptibility. Although most cases of CRMO are sporadic, there is an autosomal recessive syndromic form of the disease, called Majeed syndrome, which is due to homozygous mutations in LPIN2. In addition, there is a phenotypically similar mouse, called cmo (chronic multifocal osteomyelitis) in which the disease is inherited as an autosomal recessive disorder. The cmo locus has been mapped to murine chromosome 18. In this report, we describe phenotypic abnormalities in the cmo mouse that include bone, cartilage and skin inflammation. Utilizing a backcross breeding strategy, we refined the cmo locus to a 1.3 Mb region on murine chromosome 18. Within the refined region was the gene pstpip2, which shares significant sequence homology to the PSTPIP1. Mutations in PSTPIP1 have been shown to cause the autoinflammatory disorder PAPA syndrome (pyogenic arthritis, pyoderma gangrenosum and acne). Mutation analysis, utilizing direct sequencing, revealed a single base pair change c.293T → C in the pstpip2 gene resulting in a highly conserved leucine at amino acid 98 being replaced by a proline (L98P). No other mutations were found in the coding sequence of the remaining genes in the refined interval, although a 50 kb gap remains unexplored. These data suggest that mutations in pstpip2 may be the genetic explanation for the autoinflammatory phenotype seen in the cmo mouse.

Introduction

Autoinflammatory disorders are characterized by seemingly unprovoked inflammation in the absence of autoimmunity or infection. Chronic recurrent multifocal osteomyelitis (CRMO) [OMIM #259680] is an autoinflammatory disorder of unknown etiology. It presents in childhood with multiple, painful, sterile, inflammatory bone lesions, often accompanied by fever [1], [2]. It is frequently seen in association with other inflammatory disorders including psoriasis and inflammatory bowel disease [3], [4], [5], [6], [7], [8], [9].

Although most reported cases of CRMO are sporadic, there is evidence for a genetic component to its etiology. There are reports of affected siblings (with unaffected parents), concordance in monozygotic twins and a report of child with CRMO whose father had noninfectious osteomyelitis of the sternum [10], [11], [12], [13]. There is an autosomal recessive syndromic form of CRMO (Majeed syndrome) which is caused by mutations in LPIN2 [14], [15], [16], [17]. In addition, a CRMO susceptibility locus has been mapped to human chromosome 18q21.3–22 [13]. Furthermore, an autosomal recessive mouse model, cmo (chronic multifocal osteomyelitis) has been described and the locus has been mapped to a 21 cM region of murine chromosome 18 [18]. The cmo mice develop tail kinks and hind foot deformities caused by osteomyelitis in the affected bones. To date, the phenotypic and histologic description of this spontaneously occurring mouse model has been limited to the mouse skeletal system.

In this report, we expand the phenotypic and histologic characterization of the cmo mouse and identify a missense mutation in the pstpip2 [MGI:133508] gene that segregates with the cmo phenotype. We discuss the importance of examining the role of PSTPIP2 (the human ortholog of murine pstpip2) in the etiology of CRMO, particularly given that mutations in the related gene PSTPIP1 have been shown to cause another autoinflammatory disorder called PAPA syndrome (pyogenic arthritis, pyoderma gangrenosum and acne syndrome, MIM 604416) [19] and PSTPIP2 lies within the region containing the CRMO susceptibility locus [13].