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

Cerutti E, Campagnoli MF, Ferretti M, Garelli E, Crescenzio N, Rosolen A, Chiocchetti A, Lenardo MJ, Ramenghi U, Dianzani U - BMC Immunol. (2007)

Bottom Line: 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).Fas expression was reduced and caspase-10 activity was decreased in both patients.In both patients, the mutations were inherited from distinct healthy parents.

View Article: PubMed Central - HTML - PubMed

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

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.

Conclusion: These data strongly suggest that co-transmission of these mutation was responsible for ALPS.

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Related in: MedlinePlus

Pedigrees of Family 1 and Family 2. Inheritance of the CASP10 and TNFRSF6 mutations and electropherograms of the sequences performed on the genomic DNA of Pt.1 and Pt.2. Circles represent females; squares, males; subjects carrying a CASP10 mutation are marked in black, those with a TNFRSF6 are marked with striped lines. Numbers indicate the cell survival upon Fas triggering by mAb in T cell lines generated form each subject; Fas function was defective in Pt.1 and borderline in the other subjects (normal values of cell survival: median 60%, 95th percentile 82%)
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Figure 1: Pedigrees of Family 1 and Family 2. Inheritance of the CASP10 and TNFRSF6 mutations and electropherograms of the sequences performed on the genomic DNA of Pt.1 and Pt.2. Circles represent females; squares, males; subjects carrying a CASP10 mutation are marked in black, those with a TNFRSF6 are marked with striped lines. Numbers indicate the cell survival upon Fas triggering by mAb in T cell lines generated form each subject; Fas function was defective in Pt.1 and borderline in the other subjects (normal values of cell survival: median 60%, 95th percentile 82%)

Mentions: The pedigrees of these families are shown in the Figure 1.


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

Cerutti E, Campagnoli MF, Ferretti M, Garelli E, Crescenzio N, Rosolen A, Chiocchetti A, Lenardo MJ, Ramenghi U, Dianzani U - BMC Immunol. (2007)

Pedigrees of Family 1 and Family 2. Inheritance of the CASP10 and TNFRSF6 mutations and electropherograms of the sequences performed on the genomic DNA of Pt.1 and Pt.2. Circles represent females; squares, males; subjects carrying a CASP10 mutation are marked in black, those with a TNFRSF6 are marked with striped lines. Numbers indicate the cell survival upon Fas triggering by mAb in T cell lines generated form each subject; Fas function was defective in Pt.1 and borderline in the other subjects (normal values of cell survival: median 60%, 95th percentile 82%)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2211507&req=5

Figure 1: Pedigrees of Family 1 and Family 2. Inheritance of the CASP10 and TNFRSF6 mutations and electropherograms of the sequences performed on the genomic DNA of Pt.1 and Pt.2. Circles represent females; squares, males; subjects carrying a CASP10 mutation are marked in black, those with a TNFRSF6 are marked with striped lines. Numbers indicate the cell survival upon Fas triggering by mAb in T cell lines generated form each subject; Fas function was defective in Pt.1 and borderline in the other subjects (normal values of cell survival: median 60%, 95th percentile 82%)
Mentions: The pedigrees of these families are shown in the Figure 1.

Bottom Line: 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).Fas expression was reduced and caspase-10 activity was decreased in both patients.In both patients, the mutations were inherited from distinct healthy parents.

View Article: PubMed Central - HTML - PubMed

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

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.

Conclusion: These data strongly suggest that co-transmission of these mutation was responsible for ALPS.

Show MeSH
Related in: MedlinePlus