Genetic alterations in caspase-10 may be causative or protective in autoimmune lymphoproliferative syndrome.
Autoimmune lymphoproliferative syndrome (ALPS) is characterized by lymphadenopathy, elevated numbers of T cells with alphabeta-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.
Zhu
Shigui
S
Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, DHHS, Bethesda, MD 20892, USA.
Hsu
Amy P
AP
Vacek
Marla M
MM
Zheng
Lixin
L
Schäffer
Alejandro A
AA
Dale
Janet K
JK
Davis
Joie
J
Fischer
Roxanne E
RE
Straus
Stephen E
SE
Boruchov
Donna
D
Saulsbury
Frank T
FT
Lenardo
Michael J
MJ
Puck
Jennifer M
JM
D001327:Autoimmune Diseases / Q000209:etiology*; D053455:Caspase 10 / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005190:Family; D005260:Female; D005820:Genetic Testing; D014644:Genetic Variation; D006801:Humans; D007223:Infant; D019169:Jurkat Cells; D008232:Lymphoproliferative Disorders / Q000209:etiology*; D008297:Male; D010641:Phenotype; D013577:Syndrome; D014162:Transfection
D053455:Caspase 10; C506438:CASP10 protein, human