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PloS One 2017Chronic recurrent multifocal osteomyelitis (CRMO) is a rare, pediatric, autoinflammatory disease characterized by bone pain due to sterile osteomyelitis, and is often...
Chronic recurrent multifocal osteomyelitis (CRMO) is a rare, pediatric, autoinflammatory disease characterized by bone pain due to sterile osteomyelitis, and is often accompanied by psoriasis or inflammatory bowel disease. There are two syndromic forms of CRMO, Majeed syndrome and DIRA, for which the genetic cause is known. However, for the majority of cases of CRMO, the genetic basis is unknown. Via whole-exome sequencing, we detected a homozygous mutation in the filamin-binding domain of FBLIM1 in an affected child with consanguineous parents. Microarray analysis of bone marrow macrophages from the CRMO murine model (cmo) determined that the Fblim1 ortholog is the most differentially expressed gene, downregulated over 20-fold in the cmo mouse. We sequenced FBLIM1 in 96 CRMO subjects and found a second proband with a novel frameshift mutation in exon 6 and a rare regulatory variant. In SaOS2 cells, overexpressing the regulatory mutation showed the flanking region acts as an enhancer, and the mutation ablates enhancer activity. Our data implicate FBLIM1 in the pathogenesis of sterile bone inflammation and our findings suggest CRMO is a disorder of chronic inflammation and imbalanced bone remodeling.
Topics: Amino Acid Sequence; Animals; Cell Adhesion Molecules; Cell Line, Tumor; Child; Cytoskeletal Proteins; Female; Genes, Recessive; Humans; Interleukin-10; Mice; Mutation; Osteomyelitis; Promoter Regions, Genetic; Sequence Homology, Amino Acid
PubMed: 28301468
DOI: 10.1371/journal.pone.0169687 -
Bone Jan 2006Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory disorder that primarily affects bone but is often accompanied by inflammation of the skin and/or...
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.
Topics: Adaptor Proteins, Signal Transducing; Amino Acid Sequence; Amino Acid Substitution; Animals; Autoimmune Diseases; Chromosome Mapping; Chromosomes, Mammalian; Chronic Disease; Crosses, Genetic; Cytoskeletal Proteins; DNA Mutational Analysis; Exons; Female; Genetic Markers; Inflammation; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Microsatellite Repeats; Molecular Sequence Data; Mutation, Missense; Osteomyelitis; Proline
PubMed: 16122996
DOI: 10.1016/j.bone.2005.07.009 -
The Turkish Journal of Pediatrics 2018Sözeri B, Gerçeker-Türk B, Yıldız-Atıkan B, Mir S, Berdeli A. A novel mutation of interleukin-1 receptor antagonist (IL1RN) in a DIRA patient from Turkey:...
Sözeri B, Gerçeker-Türk B, Yıldız-Atıkan B, Mir S, Berdeli A. A novel mutation of interleukin-1 receptor antagonist (IL1RN) in a DIRA patient from Turkey: Diagnosis and treatment. Turk J Pediatr 2018; 60: 588-592. Autoinflammatory diseases can cause severe inflammation in bone and skin such as neonatal-onset multisystem inflammatory disease (NOMID), Majeed syndrome, interleukin-36 receptor antagonist deficiency (DITRA) and deficiency of interleukin-1 (IL-1) receptor antagonist (DIRA) syndrome. Here we report a five-year old boy who was admitted to the hospital with pustular skin lesions and fever in the first month of his life. Molecular analysis of IL1RN gene revealed a single homozygous C nucleotide deletion at nucleotide position 396 (p.Thr133Profs*118). The novel p.Thr133Profs*118 mutation found in our study caused frameshift mutation and as a result, the respective protein is most likely non-functional. The patient, who received a variety of treatments for various preliminary diagnoses until the final diagnosis (DIRA), was treated with recombinant IL-1Ra, anakinra, and experienced significant clinical improvement.
Topics: Child, Preschool; Hereditary Autoinflammatory Diseases; Homozygote; Humans; Immunosuppressive Agents; Interleukin 1 Receptor Antagonist Protein; Male; Mutation; Turkey
PubMed: 30968643
DOI: 10.24953/turkjped.2018.05.020