MUTATIONS OF PROGRAMMED CELL DEATH GENE FAS

Human Genome Research

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Abstract

We and our collaborators have discovered a new human disease called autoimmune lymphoproliferative syndrome (ALPS). We are studying the causes and natural history of ALPS. Patients with ALPS have large lymph nodes and spleens, increased numbers of a rare type of lymphocyte called CD4-/CD8- T cells, or double-negative T cells, and defects in programmed cell death of their lympyocytes, or lymphocyte apoptosis. We have discovered that most patients with this condition have inherited mutations in the apoptosis mediator Fas. Their lymphocytes do not die when they have finished being activated to fight infections. Instead, they accumulate and can become auto-reactive, recognizing and attacking the body's own tissues. Autoimmune diseases of the red blood cells, platelets and white blood cells are commonly seen in ALPS. We found the mutations responsible for ALPS in many patients and have learned how particular gene defects cause impairment of apoptosis by failing to transmit a death signal to the cell nucleus. Patients with no mutation in the Fas gene have in some cases been found to have defects in related genes. We have learned that the location of mutations within the Fas gene influences how severe the case of ALPS is and whether family members with the same mutation are likely to have symptoms. We have also studied mouse models for ALPS to learn how varying genetic background contributes to the disease manifestations. We have discovered that people with ALPS have a high risk of getting lymphoma.