Co-inherited mutations of Fas and caspase-10 in development of the autoimmune lymphoproliferative syndrome.
BACKGROUND
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 TCRalphabeta+ 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.


RESULTS
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.


CONCLUSIONS
These data strongly suggest that co-transmission of these mutation was responsible for ALPS.
Cerutti
Elisa
E
Interdisciplinary Research Center of Autoimmune Diseases (IRCAD) and Department of Medical Science, A, Avogadro University of Eastern Piedmont, Novara, Italy. cerutti@med.unipmn.it
Campagnoli
Maria F
MF
Ferretti
Massimo
M
Garelli
Emanuela
E
Crescenzio
Nicoletta
N
Rosolen
Angelo
A
Chiocchetti
Annalisa
A
Lenardo
Michael J
MJ
Ramenghi
Ugo
U
Dianzani
Umberto
U
D000328:Adult; D001327:Autoimmune Diseases / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D053455:Caspase 10 / Q000235:genetics*; D002460:Cell Line; D002648:Child; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D013577:Syndrome; D019014:fas Receptor / Q000235:genetics*
C491901:FAS protein, human; D019014:fas Receptor; D053455:Caspase 10