|
|
Blood, 1 September 2005, Vol. 106, No. 5, pp. 1652-1659.
Prepublished online as a Blood First Edition Paper on May 3, 2005; DOI 10.1182/blood-2004-08-3104.
 Previous Article | Table of Contents | Next Article 
IMMUNOBIOLOGY
Haploinsufficiency, rather than the effect of an excessive production of soluble CD95 (CD95 TM), is the basis for ALPS Ia in a family with duplicated 3' splice site AG in CD95 intron 5 on one allele
Joachim Roesler,
Jose-Maria Izquierdo,
Martin Ryser,
Angela Rösen-Wolff,
Manfred Gahr,
Juan Valcarcel,
Michael J. Lenardo, and
Lixin Zheng
From the Department of Pediatrics, University Clinic Carl Gustav Carus, Dresden, Germany; the Centre de Regulacio Genomica, Barcelona, Spain; and the Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
Autoimmune lymphoproliferative syndrome type Ia (ALPS Ia) is caused by mutations in the CD95/APO1/FAS (TN-FRSF6) gene, which lead to a defective CD95 ligand (CD95L)–induced apoptosis. Soluble CD95 (sCD95) has been suggested to play an important role in the pathogenesis of diverse autoimmune and malignant diseases by antagonizing CD95L. Here we evaluate a family with 4 of its 5 members harboring an ex-6–3C G mutation that affects the splice cis regulatory region (cctacag/ex-6cctagag/ex-6) of the CD95 gene. The mutation causes skipping of exon-6, which encodes the transmembrane region of CD95, and thereby leads to an excessive production of sCD95 in all 4 affected individuals. The mutation is associated with a low penetrance of disease phenotype and caused mild and transient ALPS in one male patient whereas all other family members are completely healthy. In all family members with the mutation we found that the cell surface expression of CD95 was low and the activated T cells were resistant to CD95-induced apoptosis. Unexpectedly, excessive production or addition of sCD95 had no effect on the CD95-induced apoptosis in diverse cells. In contrast, increasing the surface expression of CD95 was able to correct the defect in apoptosis. Thus we conclude that the ALPS in the one male patient was caused by haploinsufficiency of membrane CD95 expression. Our data challenge the hypothesis that sCD95 causes autoimmunity.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
I. Horie, N. Abiru, Y. Nagayama, G. Kuriya, O. Saitoh, T. Ichikawa, Y. Iwakura, and K. Eguchi
T Helper Type 17 Immune Response Plays an Indispensable Role for Development of Iodine-Induced Autoimmune Thyroiditis in Nonobese Diabetic-H2h4 Mice
Endocrinology,
November 1, 2009;
150(11):
5135 - 5142.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. M. Izquierdo and J. Valcarcel
Fas-activated Serine/Threonine Kinase (FAST K) Synergizes with TIA-1/TIAR Proteins to Regulate Fas Alternative Splicing
J. Biol. Chem.,
January 19, 2007;
282(3):
1539 - 1543.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
