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

Hereditary multiple exostoses (HME) is an autosomal dominant disorder characterized by the formation of cartilage-capped tumours (exostoses) that develop from the growth plate of endochondral bone1 This condition can lead to skeletal abnormalities, short stature and malignant transformation of exostoses to chondrosarcomas2,3 or osteosarcomas4,5 Linkage analyses have identified three different genes for HME, EXT1 on 8q241, EXT2 on 11p11–13 and EXT3 on 19p (refs 6, 7, 8, 9) Most HME cases have been attributed to missense or frameshift mutations in these tumour-supressor genes, whose functions have remained obscure Here, we show that EXT1 is an ER-resident type II transmembrane glycoprotein whose expression in cells results in the alteration of the synthesis and display of cell surface heparan sulfate glycosaminoglycans (GAGs) Two EXT1 variants containing aetiologic missense mutations10 failed to alter cell-surface glycosaminoglycans, despite retaining their ER-localization

The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate

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

Bone and cartilage and their disorders are addressed under the following headings: functions of bone; normal and abnormal bone remodeling; osteopetrosis and osteoporosis; epithelial-mesenchymal interaction, condensation and differentiation; osteoblasts, markers of bone formation, osteoclasts, components of bone, and pathology of bone; chondroblasts, markers of cartilage formation, secondary cartilage, components of cartilage, and pathology of cartilage; intramembranous and endochondral bone formation; RUNX genes and cleidocranial dysplasia (CCD); osterix; histone deacetylase 4 and Runx2; Ligand to receptor activator of NFkappaB (RANKL), RANK, osteoprotegerin, and osteoimmunology; WNT signaling, LRP5 mutations, and beta-catenin; the role of leptin in bone remodeling; collagens, collagenopathies, and osteogenesis imperfecta; FGFs/FGFRs, FGFR3 skeletal dysplasias, craniosynostosis, and other disorders; short limb chondrodysplasias; molecular control of the growth plate in endochondral bone formation and genetic disorders of IHH and PTHR1; ANKH, craniometaphyseal dysplasia, and chondrocalcinosis; transforming growth factor beta, Camurati-Engelmann disease (CED), and Marfan syndrome, types I and II; an ACVR1 mutation and fibrodysplasia ossificans progressiva; MSX1 and MSX2: biology, mutations, and associated disorders; G protein, activation of adenylyl cyclase, GNAS1 mutations, McCune-Albright syndrome, fibrous dysplasia, and Albright hereditary osteodystrophy; FLNA and associated disorders; and morphological development of teeth and their genetic mutations

The new bone biology: pathologic, molecular, and clinical correlates.

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.

Hereditary multiple exostoses (EXT) is an autosomal dominant disorder characterized by the formation of cartilage-capped prominences that develop from the growth centers of the long bones. EXT is genetically heterogeneous, with three loci, currently identified on chromosomes 8q24.1, 11p13, and 19q. The EXT1 gene, located on chromosome 8q24.1, has been cloned and is encoded by a 3.4-kb cDNA. Five mutations in the EXT1 gene have been identified--four germ-line mutations, including two unrelated families with the same mutation, and one somatic mutation in a patient with chondrosarcoma. Four of the mutations identified resulted in frameshifts and premature termination codons, while the fifth mutation resulted in a substitution of leucine for arginine. Loss of heterozygosity (LOH) analysis of chondrosarcomas and chondroblastomas revealed multiple LOH events at loci on chromosomes 3q, 8q, 10q, and 19q. One sporadic chondrosarcoma demonstrated LOH for EXT1 and EXT3, while a second underwent LOH for EXT2 and chromosome 10. A third chondrosarcoma underwent LOH for EXT1 and chromosome 3q. These results agree with previous findings that mutations at EXT1 and multiple genetic events that include LOH at other loci may be required for the development of chondrosarcoma.

Hereditary multiple exostoses (EXT): mutational studies of familial EXT1 cases and EXT-associated malignancies.

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Yang Wang

Author Tools

Chat about Author

Papers

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

Hereditary multiple exostoses (EXT): mutational studies of familial EXT1 cases and EXT-associated malignancies.