Human Genetics

, Volume 119, Issue 3, pp 284–294

Genetic alterations in caspase-10 may be causative or protective in autoimmune lymphoproliferative syndrome

Authors

  • Shigui Zhu
    • Genetics and Molecular Biology BranchNational Human Genome Research Institute
  • Amy P. Hsu
    • Genetics and Molecular Biology BranchNational Human Genome Research Institute
  • Marla M. Vacek
    • Genetics and Molecular Biology BranchNational Human Genome Research Institute
  • Lixin Zheng
    • Molecular Development SectionNational Institute of Allergy and Infectious Diseases
  • Alejandro A. Schäffer
    • Computational Biology Branch, National Center for Biotechnology InformationNational Library of Medicine
  • Janet K. Dale
    • Medical Virology Section, Laboratory of Clinical Infectious DiseasesNational Institute of Allergy and Infectious Diseases
  • Joie Davis
    • Genetics and Molecular Biology BranchNational Human Genome Research Institute
  • Roxanne E. Fischer
    • Genetics and Molecular Biology BranchNational Human Genome Research Institute
  • Stephen E. Straus
    • Medical Virology Section, Laboratory of Clinical Infectious DiseasesNational Institute of Allergy and Infectious Diseases
  • Donna Boruchov
    • Division of Pediatric Hematology and Oncology, Department of PediatricsBrookdale University Hospital Medical Center
  • Frank T. Saulsbury
    • Department of PediatricsUniversity of Virginia Health System
  • Michael J. Lenardo
    • Molecular Development SectionNational Institute of Allergy and Infectious Diseases
    • Genetics and Molecular Biology BranchNational Human Genome Research Institute
    • GMBB
Original Investigation

DOI: 10.1007/s00439-006-0138-9

Cite this article as:
Zhu, S., Hsu, A.P., Vacek, M.M. et al. Hum Genet (2006) 119: 284. doi:10.1007/s00439-006-0138-9

Abstract

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by lymphadenopathy, elevated numbers of T cells with αβ-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 Americans, 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.

Copyright information

© Springer-Verlag 2006