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Characterization of a novel combined immunodeficiency with skeletal dysplasia

一种新型联合免疫缺陷伴骨骼发育不良的特征

基本信息

批准号：
8995190
负责人：
Luigi Daniele Notarangelo
金额：
$ 22.13万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-15 至 2016-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8995190
关键词：
Affect Architecture Autoantigens Autologous Biological Branchial arch structure CD4 Positive T Lymphocytes CD8B1 gene CRISPR/Cas technology Cartilage Cell surface Cells Data Defect Development Disease Disease model Dysplasia Elderly Eosinophilia Exfoliative Dermatitis FOXP3 gene Family Female Gene Mutation Generations Genes Hair Health Hematopoietic Stem Cell Transplantation Heparan Sulfate Biosynthesis Heparan Sulfate Proteoglycan Heparitin Sulfate Human IgE Immune Immune system Immunity Immunologic Deficiency Syndromes In Vitro Infant Infection Lead Limb Bud Link Lymphatic Diseases Lymphopenia Mesenchyme Missense Mutation Mitogens Molecular Mus Mutation Neural Crest Organogenesis Parents Patients Pectoral Peripheral Phenotype Play Proteoglycan Recurrence Regulatory T-Lymphocyte Reporting Role Serum Severe Combined Immunodeficiency Siblings Skeletal Development Syndrome System Systems Development T cell differentiation T-Cell Development T-Lymphocyte Technology Testing Therapeutic Thymic epithelial cell Thymus Gland Tissues Zebrafish base cell type congenital immunodeficiency disease phenotype exome sequencing gene correction glycosyltransferase induced pluripotent stem cell insight male member morphogens mouse model mutant novel polysulfated glycosaminoglycan skeletal skeletal dysplasia thymocyte thymus transplantation transcription factor

项目摘要

DESCRIPTION (provided by applicant): Immuno-osseous dysplasias (IOD) are a group of disorders characterized by immune deficiency and skeletal dysplasia. Schimke's disease (SIOD) and cartilage hair hypoplasia (CHH) represent the prototypic forms of these disorders, but several other cases of IOD with unknown molecular basis have been described. The immunodeficiency seen in IOD is often severe, and affects predominantly T lymphocytes. Immune dysregulation typical of Omenn syndrome (OS) has been reported in some patients with CHH. We have identified and studied two siblings (a male and a female) with rapidly progressive and fatal IOD. Both infants manifested T cell lymphopenia with markedly reduced number of CD8+ T cells, lack of proliferation to mitogens, hypogammaglobulinemia, increased serum IgE and eosinophilia. The elder sibling had features of OS, with erythroderma and expansion of oligoclonal and activated CD4+ T cells. No mutations were identified in the SMARCAL1 and RMRP genes, responsible for SIOD and CHH, respectively. Whole exome sequencing (WES) revealed that both siblings were homozygous, and both parents heterozygous, for a novel and drastic missense mutation (R339W) affecting a highly conserved residue of Exostosin-like 3 (EXTL3), a member of the exostosin (EXT) family of glycosyltransferases involved in heparan sulfate (HS) biosynthesis. HS are sulfated glycosaminoglycans that decorate cell surface and matrix proteoglycans. HS proteoglycans modulate the activity of morphogens that play a key role in skeletal development and T cell differentiation. Our overall hypothesis is that EXTL3 is critical for thymic development and that EXTL3 mutations in humans cause a novel form of IOD. In support of our hypothesis, our preliminary data demonstrate that EXTL3 is expressed by human thymocytes, thymic epithelial cells (TECs), and peripheral T cells. Moreover, mutation of Extl3 in zebrafish causes defects of limb bud development, and impaired thymic T cell development. To test our hypothesis, and to investigate the cellular basis of the immunodeficiency associated with EXTL3 mutations, we will generate and characterize mouse models with tissue-specific disruption of the Extl3 gene in neural crest mesenchyme cells, TECs, or thymocytes. All of these cell types produce HS and are critically involved in thymus organogenesis and T cell development. In parallel, in order to demonstrate the disease-causing effect of the EXTL3 p.R339W mutation identified in the affected siblings, we will perform disease modeling using patient-derived induced pluripotent stem cells (iPSCs). We will use the CRISPR/Cas9 technology to correct the EXTL3 p.R339W mutation in patient-derived iPSCs. In order to define the cell autonomous effect of the EXTL3 mutation, we will differentiate both mutant and gene-corrected iPSCs to TECs and T cells, and we will study HS biosynthesis under the same experimental conditions. We anticipate that this study will provide novel important insights on the biological role of HSPGs in immune system development and function, and will help define the optimal therapeutic approach to correct the immunodeficiency of this condition.