This project investigates the nature of mutations causing severe combined immunodeficiency, the Boy in the Bubble Disease and also studies the effect of this disease on the patient and family. SCID is most often caused by defects in the IL2RG gene which encodes the common gamma chain of receptors for cytokines. When this gene is defective, lymphocytes do not develop normally, and affected infants have 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). 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 in these patients. We perform carrier testing and genetic counseling, and in some instances prenatal diagnosis to make affected infants eligible for improved early treatments. In the past year we have developed a new assay for testing function of the signaling pathway that is defective in X-linked SCID. We also have studied the psychology of patients and their family members to measure the impact of this condition and develop ways physicians may help families cope better.

National Institute of Health (NIH)
National Human Genome Research Institute (NHGRI)
Intramural Research (Z01)
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Human Genome Research
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Chan, Kee; Puck, Jennifer M (2005) Development of population-based newborn screening for severe combined immunodeficiency. J Allergy Clin Immunol 115:391-8
Chinen, Javier; Puck, Jennifer M (2004) Perspectives of gene therapy for primary immunodeficiencies. Curr Opin Allergy Clin Immunol 4:523-7
Chinen, Javier; Puck, Jennifer M (2004) Successes and risks of gene therapy in primary immunodeficiencies. J Allergy Clin Immunol 113:595-603; quiz 604
Hale, Laura P; Buckley, Rebecca H; Puck, Jennifer M et al. (2004) Abnormal development of thymic dendritic and epithelial cells in human X-linked severe combined immunodeficiency. Clin Immunol 110:63-70
Notarangelo, Luigi; Casanova, Jean-Laurent; Fischer, Alain et al. (2004) Primary immunodeficiency diseases: an update. J Allergy Clin Immunol 114:677-87
Matsuzaki, Hajime; Loi, Halina; Dong, Shoulian et al. (2004) Parallel genotyping of over 10,000 SNPs using a one-primer assay on a high-density oligonucleotide array. Genome Res 14:414-25
Cooper, Max D; Lanier, Lewis L; Conley, Mary Ellen et al. (2003) Immunodeficiency disorders. Hematology Am Soc Hematol Educ Program :314-30
Myers, Laurie A; Patel, Dhavalkumar D; Puck, Jennifer M et al. (2002) Hematopoietic stem cell transplantation for severe combined immunodeficiency in the neonatal period leads to superior thymic output and improved survival. Blood 99:872-8
Vihinen, M; Arredondo-Vega, F X; Casanova, J L et al. (2001) Primary immunodeficiency mutation databases. Adv Genet 43:103-88
Fanos, J H; Davis, J; Puck, J M (2001) Sib understanding of genetics and attitudes toward carrier testing for X-linked severe combined immunodeficiency. Am J Med Genet 98:46-56

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