Growth retardation resulting in short stature is a major concern for parents and due to its great variety of causes, a complex diagnostic challenge for clinicians. A major locus involved in linear growth has been implicated within the pseudoautosomal region (PAR1) of the human sex chromosomes. We have determined an interval of 170 kb of DNA within PAR1 which was deleted in 36 individuals with short stature and different rearrangements on Xp22 or Yp11.3. This deletion was not detected in any of the relatives with normal stature or in a further 30 individuals with rearrangements on Xp22 or Yp11.3 with normal height. We have isolated a homeobox-containing gene (SHOX) from this region, which has at least two alternatively spliced forms, encoding proteins with different patterns of expression. We also identified one functionally significant SHOX mutation by screening 91 individuals with idiopathic short stature. Our data suggest an involvement of SHOX in idiopathic growth retardation and in the short stature phenotype of Turner syndrome patients.

Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome

The growth factor progranulin (PGRN) has been implicated in embryonic development, tissue repair, tumorigenesis, and inflammation, but its receptors remain unidentified. We report that PGRN bound directly to tumor necrosis factor receptors (TNFRs) and disturbed the TNFα-TNFR interaction. PGRN-deficient mice were susceptible to collagen-induced arthritis, and administration of PGRN reversed inflammatory arthritis. Atsttrin, an engineered protein composed of three PGRN fragments, exhibited selective TNFR binding. PGRN and Atsttrin prevented inflammation in multiple arthritis mouse models and inhibited TNFα-activated intracellular signaling. Collectively, these findings demonstrate that PGRN is a ligand of TNFR, an antagonist of TNFα signaling, and plays a critical role in the pathogenesis of inflammatory arthritis in mice. They also suggest new potential therapeutic interventions for various TNFα-mediated pathologies and conditions, including rheumatoid arthritis.

/pdf/the-growth-factor-progranulin-binds-to-tnf-receptors-and-is-21puppsdsi.pdf

The Growth Factor Progranulin Binds to TNF Receptors and Is Therapeutic Against Inflammatory Arthritis in Mice

Thrombospondins are evolutionarily conserved, calcium-binding glycoproteins that undergo transient or longer-term interactions with other extracellular matrix components.They share properties with other matrix molecules, cytokines, adaptor proteins, and chaperones, modulate the organization of collagen fibrils, and bind and localize an array of growth factors or proteases.At cell surfaces, interactions with an array of receptors activate celldependent signaling and phenotypic outcomes.Through these dynamic, pleiotropic, and context-dependent pathways, mammalian thrombospondins contribute to wound healing and angiogenesis, vessel wall biology, connective tissue organization, and synaptogenesis.We overview the domain organization and structure of thrombospondins, key features of their evolution, and their cell biology.We discuss their roles in vivo, associations with human disease, and ongoing translational applications.In many respects, we are only beginning to appreciate the important roles of these proteins in physiology and pathology.T hrombospondins (TSPs) comprise a con- served family of extracellular, oligomeric, multidomain, calcium-binding glycoproteins.In general, basal metazoa and protostomes encode a single TSP in their genomes and deuterostomes have multiple TSP genes.The TSPs of mammals have many complex tissue-specific roles, including activities in wound healing and angiogenesis, vessel wall biology, connective tissue organization, and synaptogenesis.These activities derive mechanistically from interactions with cell surfaces, growth factors, cytokines, or components of the extracellular matrix (ECM) that collectively regulate many aspects of cell phenotype.Emerging evidence on the functions of TSPs in invertebrates suggests that ancient functions include bridging activities in cell-cell and cell-ECM interactions.Knowledge of TSP domain structures provides a rational basis for understanding their roles in vivo and associations with human disease and is assisting ongoing translational applications. 

The Thrombospondins

Mutations in Cartilage Oligomeric Matrix Protein Causing Pseudoachondroplasia and Multiple Epiphyseal Dysplasia Affect Binding of Calcium and Collagen I, II, and IX

A thrombospondin-dependent pathway for a protective ER stress response

Pseudoachondroplasia (PSACH) is a well characterized dwarfing condition mapping to chromosome 19p12-13.1. Cartilage oligomeric matrix protein (COMP), a cartilage specific protein, maps to the same location within a contig that spans the PSACH locus. Using single strand conformation polymorphism (SSCP) analysis and nucleotide sequencing we have identified COMP mutations in eight familial and isolated PSACH cases. All mutations involve either a single base-pair change or a three base-pair deletion in exon 17B. Six mutations delete or change a well conserved aspartic acid residue within the calcium-binding type 3 repeats. These results demonstrate that mutations in the COMP gene cause pseudochondroplasia.

Mutations in exon 17B of cartilage oligomeric matrix protein (COMP) cause pseudoachondroplasia.

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Mutations in exon 17B of cartilage oligomeric matrix protein (COMP) cause pseudoachondroplasia.