Cerutti, Elisa - Campagnoli, Maria F - Ferretti, Massimo - Garelli, Emanuela - Crescenzio, Nicoletta - Rosolen, Angelo - Chiocchetti, Annalisa - Lenardo, Michael J - Ramenghi, Ugo - Dianzani, Umberto (2007) Co-inherited mutations of Fas and caspase-10 in development of the autoimmune lymphoproliferative syndrome. [Articolo di periodico (online)]
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Autoimmune lymphoproliferative syndrome (ALPS) is a rare inherited disorder characterized by defective function of Fas, autoimmune manifestations that predominantly involve blood cells, polyclonal accumulation of lymphocytes in the spleen and lymph nodes with lymphoadenomegaly and/or splenomegaly, and expansion of TCR??+ CD4/CD8 double-negative (DN) T cells in the peripheral blood. Most frequently, it is due to Fas gene mutations, causing ALPS type Ia (ALPS-Ia). However, other mutations, namely of the FasL gene (ALPS-Ib) and the caspase-10 gene (ALPS-II) are occasionally detected, whereas some patients do not present any known mutations (ALPS-III). Recently, mutations of the NRAS gene have been suggested to cause ALPS-IV.
This work reports two patients that are combined heterozygous for single nucleotide substitutions in the Fas and caspase-10 genes. The first patient carried a splice site defect suppressing allele expression in the Fas gene and the P501L substitution in caspase-10. The second had a mutation causing a premature stop codon (Q47X) in the Fas gene and the Y446C substitution in caspase-10. Fas expression was reduced and caspase-10 activity was decreased in both patients. In both patients, the mutations were inherited from distinct healthy parents.
These data strongly suggest that co-transmission of these mutation was responsible for ALPS.
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