MUTATIONS OF PROGRAMMED CELL DEATH GENE FAS

Human Genome Research

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Abstract

Inherited diseases are often uncommon in themselves, but a good source of insight for understanding common, complex diseases. We study the genetic disease autoimmune lymphoproliferative syndrome (ALPS) to learn about mechanisms of autoimmune disease. 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, or apoptosis of their lymphocytes. We have found that most patients with ALPS 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 attack 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, including multiple members of families where some people are more severely affected than others. Modifying genes that influence how bad ALPS can be are being sought. Patients with no mutation in the Fas gene have in some cases been found to have defects in related genes. We have also learned that the type of mutation 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. As part of this project mouse models for ALPS are studied 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.