Gene Cloning: Pediatric Bone Marrow Transplant Program

Severe Combined Immunodeficiency Disease (SCID) is a group of heterogeneous inherited diseases of the immune system resulting in severe and usually fatal infections (sometimes referred to as "bubble babies"). The incidence of SCID in the Navajo and Apache Nations (collectively known as Athabascan-speaking Native Americans) is among the highest of any inherited disease. The UCSF Pediatric BMT Program has cared for more than 20 Athabascan-speaking children with SCID. In 1998 we located the "SCIDA" gene on human chromosome 10 and recently cloned it and proved that it is uniquely responsible for the development of this disease.

Benefits to isolating the SCIDA (Athabascan SCID) gene

The cloning of the gene and identification of a unique mutation resulting in SCIDA allowed us to develop a rapid test for those children affected with the disease as well as the identification of unaffected carriers. The early diagnosis of SCID is crucial for the successful use of bone marrow transplantation in these children.

Now that we have identified the disease gene and developed methods to detect the mutation in genomic DNA for carrier detection, prenatal diagnosis and early therapeutic intervention (bone marrow transplant), we are beginning the process of studying the gene and developing gene therapy. Also, a better understanding of Athabascan SCID could lead to a more general understanding of the causes of the T^-B^-phenotype. We have begun studies of this novel gene that we now know is intimately involved in the maturation of T and B lymphocytes as well as the repair of damaged DNA.

Finally, since this genetic mutation results in an extremely specific defect that is selective for the immune system, identification of the gene could lead to a better understanding of immune regulation and could result in novel approaches to treating diseases of immune dysregulation and certain cancers.

Mouse Model of SCIDA

After cloning the mouse equivalent of SCIDA in humans we engineered a mutation in the gene that mimicked that found in the Navajos and Apaches. Recently, we have had our first liters of "Scida" mice! We are now studying these healthy-appearing animals to determine to what extent they will be like children with the disease. This unique animal model will be critical in helping us to not only understand the role that this gene plays in the normal development and functioning of the immune system but also how is helps the body repair damage that occurs to our DNA during the normal process of day to day living. This animal model can also help us to develop better ways to treat children with a variety of immunodeficiency diseases using bone marrow transplantation both pre- and postnatally and to develop an approach using gene therapy to cure this disease.

Athabascan-speaking Native Americans

The Navajo and Apache Indians are part of the Athabascan linguistic group of native Americans who migrated to the Southwestern United States from Alaska and Canada between 700-l500AD. In l864, the Navajo Nation was reduced to an estimated 4,000 individuals living in relatively isolated family units. Since then, they have become the fastest-growing population in North America and currently number approximately 200,000 people. The Navajo are an endogamous people divided into 50-60 clans (2-4000/clan). The Navajo society is matriarchal and matrilineal with clan identification following maternal lines. It is believed that all Athabascan-speaking peoples originated in Asia and crossed into North America via the Bering land mass.

We have identified two Athabascan-speaking families from the Dogrib Indians, living in the Canadian Northwest Territories who have had three children with SCID. Both the immunologic and clinical phenotypes in these children are identical to those in the Navajo and Apache. The genetic closeness of Athabascans in the Southwestern United States with those in the Northwest Territories, i.e., the Dogrib, has been suggested by studies of a variety of genetic markers.

Athabascan SCID

While the incidence of some inherited diseases (such as cystic fibrosis) is very low in the Navajo and Apache, there is a uniquely high incidence of SCID. Athabascan SCID is inherited as an autosomal recessive disease with an estimated incidence of l:2,000 live births and an estimated gene frequency of 2.1%. This is compared to the estimated incidence of l:500,000 for autosomal recessive SCID among outbred populations and l:l0,000 for first cousin marriages. Attempts to identify a specific inborn error of metabolism, e.g., adenosine deaminase (ADA) or purine nucleoside phosphorylase (PNP) deficiency in the Navajo and Apache children with SCID have been unsuccessful.