New gene mutation found to cause 'bubble boy disease'

Approximately one in every million people develop a group of inherited disorders known as severe combined immunodeficiency (SCID) or "bubble boy disease". Characterized by inherited abnormal changes in B and T cells of their immune system, these individuals often suffer from numerous serious or life-threatening infections that are often fatal in early life. The condition became widely known in the 1970's when the world learned of David Vetter, a boy with SCID who lived for 12 years in a plastic, germ-free bubble.

A number of genetic abnormalities can cause SCID. The two most common forms are linked to the X chromosome. Patients with abnormalities on this chromosome either lack an enzyme called adenosine deaminase, or lack the ability to produce IL-2 receptor gamma chain, a molecule that T cells need to communicate with B cells. In some cases of SCID, doctors have been unable to identify the underlying cause.

In the November 15 issue of the Journal of Clinical Investigation, Françoise Le Deist and colleagues from INSERM, Paris, describe how a complete deficiency in the CD3 epsilon chain of the T cell receptor, which binds foreign antigens and thus targets them for destruction, causes SCID.

The authors studied 3 families with, or having had lost, infants with SCID of an unknown molecular type. All of these individuals had normal B cells but no T cells. The authors found that the absence of CD3 epsilon completely blocks T cell development at a specific stage in the thymus.

In an accompanying commentary, Rebecca H. Buckley, a pediatrician at Duke University Medical Center, discusses the importance of the identification of this new mutation. "If the diagnosis is made at birth or shortly thereafter, definitive therapy in the form of bone marrow stem cell transplantation can result in a survival rate as high as 97%, regardless of the molecular type of SCID." Dr. Buckley cautions that while stem cell transplantation (involving transplanting bone marrow from a healthy sibling or other donor whose tissue type closely matches that of the patient's) is not a perfect therapy, there has been remarkable success in reestablishing the B and T cell population in SCID patients. However, gene therapy cannot be performed unless the abnormal gene for the specific patient is known. At Duke University alone, approximately 6% of recorded SCID cases have an unknown molecular basis. Identification of this new mutation in the CD3 epsilon chain will prompt doctors to examine such individuals for this mutation and hopefully allow suitable therapeutic steps, such as gene therapy, to be considered.

TITLE: Severe combined immunodeficiency caused by deficiency in either the d or e subunit of CD3.

AUTHOR CONTACT: Françoise Le Deist
INSERM and Hôpital Necker-Enfants Malades, Paris, France.
Phone: 33-1-44-49-50-88; Fax: 33-1-42-73-06-40; E-mail: francoise.ledeist@nck.ap-hop-paris.fr.

View the PDF of this article at: http://www.jci.org/cgi/content/full/114/10/1512

ACCOMPANYING COMMENTARY:

TITLE: The multiple causes of human SCID

AUTHOR CONTACT: Rebecca H. Buckley
Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.
Phone: 919-684-2922; Fax: 919-681-7979; E-mail: buckL003@mc.duke.edu.

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