@article {635, title = {Recessive coding and regulatory mutations in FBLIM1 underlie the pathogenesis of chronic recurrent multifocal osteomyelitis (CRMO).}, journal = {PLoS One}, volume = {12}, year = {2017}, month = {2017}, pages = {e0169687}, abstract = {

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.

}, keywords = {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}, issn = {1932-6203}, doi = {10.1371/journal.pone.0169687}, author = {Cox, Allison J and Darbro, Benjamin W and Laxer, Ronald M and Velez, Gabriel and Bing, Xinyu and Finer, Alexis L and Erives, Albert and Mahajan, Vinit B and Bassuk, Alexander G and Ferguson, Polly J} } @article {115, title = {Calpain-5 mutations cause autoimmune uveitis, retinal neovascularization, and photoreceptor degeneration.}, journal = {PLoS Genet}, volume = {8}, year = {2012}, month = {2012}, pages = {e1003001}, abstract = {

Autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) is an autoimmune condition of the eye that sequentially mimics uveitis, retinitis pigmentosa, and proliferative diabetic retinopathy as it progresses to complete blindness. We identified two different missense mutations in the CAPN5 gene in three ADNIV kindreds. CAPN5 encodes calpain-5, a calcium-activated cysteine protease that is expressed in retinal photoreceptor cells. Both mutations cause mislocalization from the cell membrane to the cytosol, and structural modeling reveals that both mutations lie within a calcium-sensitive domain near the active site. CAPN5 is only the second member of the large calpain gene family to cause a human Mendelian disorder, and this is the first report of a specific molecular cause for autoimmune eye disease. Further investigation of these mutations is likely to provide insight into the pathophysiologic mechanisms of common diseases ranging from autoimmune disorders to diabetic retinopathy.

}, keywords = {Amino Acid Sequence, Base Sequence, Calpain, Cell Line, Cells, Cultured, Choroid Diseases, Exome, Exons, Eye Diseases, Hereditary, Female, Gene Expression, Genetic Linkage, Humans, Male, Models, Molecular, Molecular Sequence Data, Mutation, Pedigree, Phenotype, Photoreceptor Cells, Vertebrate, Protein Conformation, Protein Transport, Retinal Degeneration, Sequence Alignment}, author = {Mahajan, Vinit B and Skeie, Jessica M and Bassuk, Alexander G and Fingert, John H and Braun, Terry A and Daggett, Heather T and Folk, James C and Sheffield, Val C and Stone, Edwin M} } @article {831, title = {Connectin: a homophilic cell adhesion molecule expressed on a subset of muscles and the motoneurons that innervate them in Drosophila.}, journal = {Cell}, volume = {70}, year = {1992}, month = {1992 Aug 21}, pages = {553-67}, abstract = {

Each abdominal hemisegment in the Drosophila embryo contains a stereotyped array of 30 muscles, each specifically innervated by one or a few motoneurons. We screened 11,000 enhancer trap lines, isolated several expressing beta-galactosidase in small subsets of muscle fibers prior to innervation, and identified two of these as inserts in connectin and Toll, members of the leucine-rich repeat gene family. Connectin contains a signal sequence, ten leucine-rich repeats, and a putative phosphatidylinositol membrane linkage; in S2 cells, connectin can mediate homophilic cell adhesion. Connectin is expressed on the surface of eight muscles, the motoneurons that innervate them, and several glial cells along the pathways leading to them. During synapse formation, the protein localizes to synaptic sites; afterward, it largely disappears. Thus, connectin is a novel cell adhesion molecule whose expression suggests a role in target recognition.

}, keywords = {Amino Acid Sequence, Animals, Base Sequence, Cell Adhesion Molecules, Cloning, Molecular, Connectin, DNA, Drosophila, Molecular Sequence Data, Motor Neurons, Muscle Proteins, Muscles, Protein Kinases, Sequence Alignment}, issn = {0092-8674}, author = {Nose, A and Mahajan, V B and Goodman, C S} }