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

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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.

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Acknowledgements

The authors thank participating ALPS family members. They also thank Kusum Viswanathan for his diagnosis and referral of one of the probands, and Koneti Rao, Fred Gill and Faith Dugan for patient management, Dan Kastner for TNFRSF1A consultation, Maggie Brown and Tom Fleisher for cell surface phenotype analysis, Stacie Anderson and Martha Kirby for apoptosis assays, and Gretchen Gibney for assistance with data management. This research was supported by the Intramural Research Programs of the NHGRI, NIAID and NLM, National Institutes of Health.

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Authors and Affiliations

  1. Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, DHHS, Bethesda, MD, USA

    Shigui Zhu, Amy P. Hsu, Marla M. Vacek, Joie Davis, Roxanne E. Fischer & Jennifer M. Puck

  2. Molecular Development Section, National Institute of Allergy and Infectious Diseases, NIH, DHHS, Bethesda, MD, USA

    Lixin Zheng & Michael J. Lenardo

  3. Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, NIH, DHHS, Bethesda, MD, USA

    Alejandro A. Schäffer

  4. Medical Virology Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, DHHS, Bethesda, MD, USA

    Janet K. Dale & Stephen E. Straus

  5. Division of Pediatric Hematology and Oncology, Department of Pediatrics, Brookdale University Hospital Medical Center, Brooklyn, NY, USA

    Donna Boruchov

  6. Department of Pediatrics, University of Virginia Health System, Charlottesville, VA, USA

    Frank T. Saulsbury

  7. GMBB, Bldg. 49, Room 4A14, 49 Convent Drive, Bethesda, MD, 20892, USA

    Jennifer M. Puck

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  1. Shigui Zhu
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  2. Amy P. Hsu
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  3. Marla M. Vacek
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  4. Lixin Zheng
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  5. Alejandro A. Schäffer
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  6. Janet K. Dale
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  7. Joie Davis
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  8. Roxanne E. Fischer
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  9. Stephen E. Straus
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  10. Donna Boruchov
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  11. Frank T. Saulsbury
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  12. Michael J. Lenardo
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  13. Jennifer M. Puck
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Correspondence to Jennifer M. Puck.

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Zhu, S., Hsu, A.P., Vacek, M.M. et al. Genetic alterations in caspase-10 may be causative or protective in autoimmune lymphoproliferative syndrome. Hum Genet 119, 284–294 (2006). https://doi.org/10.1007/s00439-006-0138-9

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  • DOI: https://doi.org/10.1007/s00439-006-0138-9

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