title: Co-inherited mutations of Fas and caspase-10 in development of the autoimmune lymphoproliferative syndrome.
abstract: 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.
authors.affiliation: Interdisciplinary Research Center of Autoimmune Diseases (IRCAD) and Department of Medical Science, A, Avogadro University of Eastern Piedmont, Novara, Italy. cerutti@med.unipmn.it
authors.forename: Elisa
authors.initials: E
authors.lastname: Cerutti
authors.forename: Maria F
authors.initials: MF
authors.lastname: Campagnoli
authors.forename: Massimo
authors.initials: M
authors.lastname: Ferretti
authors.forename: Emanuela
authors.initials: E
authors.lastname: Garelli
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Crescenzio
authors.forename: Angelo
authors.initials: A
authors.lastname: Rosolen
authors.forename: Annalisa
authors.initials: A
authors.lastname: Chiocchetti
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lenardo
authors.forename: Ugo
authors.initials: U
authors.lastname: Ramenghi
authors.forename: Umberto
authors.initials: U
authors.lastname: Dianzani
mesh_terms: 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*
chemical_list: C491901:FAS protein, human; D019014:fas Receptor; D053455:Caspase 10