This project investigates the nature of mutations in X-linked severe combined immunodeficiency (the Boy in the Bubble Disease, also called XSCID) and related disorders. XSCID is caused by defects in the IL2RG gene which encodes the common gamma chain of receptors for cytokines. When this gene is defective, lymphocytes cannot develop normally, and affected infants develop frequent, severe infections that are ultimately fatal unless the immune system can be restored. Bone marrow transplant is often life-saving, and gene therapy is a promising treatment (see related project ZO1-HG-00033-06). In order to know how mutations in the IL2RG gene cause disease, we enroll patients or their family members, collect samples of blood or tissue, perform DNA analysis, assess expression of common gamma chain protein, analyze function of this protein and correlate the results. We have learned that mutations occur in all exons of the gene. Some unusual mutations give clues to how the gene normally interacts with other proteins on the surface of the cell and in the cytoplasm of the cell. Certain mutations permit residual gamma chain function and have a distinct clinical picture both in disease characteristics and response to standard treatment. Patients with SCID but with no mutation in the X-linked gene may have related genetic disorders, and we investigate other genes these patients. We perform carrier testing and genetic counseling, and in some instances prenatal diagnosis to make affected infants eligible for improved early treatments.
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