ORIGINAL INVESTIGATION Shigui Zhu Æ Amy P. Hsu Æ Marla M. Vacek Lixin Zheng Æ Alejandro A. Scha¨ffer Æ Janet K. Dale Joie Davis Æ Roxanne E. Fischer Æ Stephen E. Straus Donna Boruchov Æ Frank T. Saulsbury Michael J. Lenardo Æ Jennifer M. Puck Genetic alterations in caspase-10 may be causative or protective in autoimmune lymphoproliferative syndrome Received: 2 October 2005 / Accepted: 4 January 2006 / Published online: 31 January 2006 Ó Springer-Verlag 2006 Abstract Autoimmune lymphoproliferative syndrome (ALPS) is characterized by lymphadenopathy, elevated numbers of T cells with ab-T cell receptors but neither CD4 nor CD8 co-receptors, and impaired lymphocyte apoptosis in vitro. Defects in the Fas receptor are the most common cause of ALPS (ALPS Ia), but in rare cases other apoptosis proteins have been implicated, including caspase-10 (ALPS II). We investigated the role of variants of caspase-10 in ALPS. Of 32 unrelated probands with ALPS who did not have Fas defects, two were heterozygous for the caspase-10 missense mutation I406L. Like the previously reported ALPS II-associated mutation L285F, I406L impaired apoptosis when transfected alone and dominantly inhibited apoptosis mediated by wild type caspase-10 in a co-transfection assay. Other variants in caspase-10, V410I and Y446C, were found in 3.4 and 1.6% of chromosomes in Caucasians, and in 0.5 and <0.5% of African Amer- icans, respectively. In contrast to L285F and I406L, these variants had no dominant negative effect in co-transfection assays into the H9 lymphocytic cell line. We found healthy individuals homozygous for V410I, challenging the earlier suggestion that homozygosity for V410I alone causes ALPS. Moreover, an association analysis suggested protection from severe disease by caspase-10 V410I in 63 families with ALPS Ia due to dominant Fas mutations (P<0.05). Thus, different genetic variations in caspase-10 can produce contrasting phenotypic effects. Introduction Autoimmune lymphoproliferative syndrome (ALPS) is defined by the triad of chronic non-malignant enlarge- ment of spleen and lymph nodes; increased numbers of T cells bearing ab T cell receptors, but expressing neither the CD4 nor CD8 surface determinants (double negative T cells or DNTs); and defective in vitro apoptosis of mature lymphocytes (Fisher et al. 1995; Rieux-Laucat et al. 1995; Drappa et al. 1996; Jackson et al. 1999; Puck and Zhu 2003; Sneller et al. 2003; Bleesing and Puck 2004). Individuals with ALPS frequently suffer autoim- mune complications, primarily hemolytic anemia and thrombocytopenia. They also have an elevated incidence of diverse types of lymphoma (Straus et al. 2001). Most cases of ALPS are associated with dominant, heterozy- gous mutations of the apoptosis receptor Fas (CD95), encoded by tumor necrosis factor receptor superfamily S. Zhu Æ A. P. Hsu Æ M. M. Vacek Æ J. Davis R. E. Fischer Æ J. M. Puck Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, DHHS, Bethesda, MD, USA L. Zheng Æ M. J. Lenardo Molecular Development Section, National Institute of Allergy and Infectious Diseases, NIH, DHHS, Bethesda, MD, USA A. A. Scha¨ffer Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, NIH, DHHS, Bethesda, MD, USA J. K. Dale Æ S. E. Straus Medical Virology Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, DHHS, Bethesda, MD, USA D. Boruchov Division of Pediatric Hematology and Oncology, Department of Pediatrics, Brookdale University Hospital Medical Center, Brooklyn, NY, USA F. T. Saulsbury Department of Pediatrics, University of Virginia Health System, Charlottesville, VA, USA J. M. Puck (&) GMBB, Bldg. 49, Room 4A14, 49 Convent Drive, Bethesda, MD 20892, USA E-mail: jpuck@mail.nih.gov Tel.: +1-301-4022194 Fax: +1-301-4024929 Hum Genet (2006) 119: 284–294 DOI 10.1007/s00439-006-0138-9