title: 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.
authors.affiliation: Department of Pediatrics, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242, USA. polly-ferguson@uiowa.edu
authors.forename: Polly J
authors.initials: PJ
authors.lastname: Ferguson
authors.forename: Xinyu
authors.initials: X
authors.lastname: Bing
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Vasef
authors.forename: Luis A
authors.initials: LA
authors.lastname: Ochoa
authors.forename: Amar
authors.initials: A
authors.lastname: Mahgoub
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Waldschmidt
authors.forename: Lorraine T
authors.initials: LT
authors.lastname: Tygrett
authors.forename: Annette J
authors.initials: AJ
authors.lastname: Schlueter
authors.forename: Hatem
authors.initials: H
authors.lastname: El-Shanti
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian; D002908:Chronic Disease; D003433:Crosses, Genetic; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000235:genetics*; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D005819:Genetic Markers; D007249:Inflammation / Q000235:genetics*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010019:Osteomyelitis / Q000235:genetics*; D011392:Proline / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D005819:Genetic Markers; C486383:Pstpip2 protein, mouse; D011392:Proline