The Autoimmune Lymphoproliferative Syndrome (ALPS) Associated with a Novel Mutation in Exon 6 of the FAS (TNFRSF6) Gene (35.14)

Abstract

ALPS is the result of dysregulated lymphocyte FAS-mediated apoptosis and is characterized by lymphadenopathy, autoimmune phenomena, the expansion of a CD3+/CD4−CD8− T cell population, hypergammaglobulinemia, and an increased risk for lymphoma. We present the laboratory and clinical studies of a 6 y/o female with a history of adenopathy, severe neutropenia, microcytic anemia, and recurrent systemic infections. She has hypergammaglobulinemia (IgG = 2020 mg/dL; IgM = 413; IgA = 695 mg/dL), an elevated RF, an elevated CD3+/CD4−CD8− lymphocyte fraction, normal in vitro lymphocyte proliferation and normal titers to tetanus, diphtheria and pneumococcal antigens. Bone marrow aspirate and biopsy were unremarkable. We suspected a diagnosis of ALPS; therefore, exons 1–9 of the FAS (TNFRSF6) gene were PCR-amplified from genomic DNA. Bidirectional sequencing demonstrated a novel heterozygous mutation, I184V, an A>G change resulting in a substitution of the normal isoleucine codon (ATT) with a mutant valine codon (GTT) in exon 6. This is a previously unpublished mutation in association with ALPS. The presence of the I184V mutation was confirmed by restriction fragment analysis using the Bsr1 endonuclease. This A>G mutation appears to create a splice acceptor site that could strongly compete with the actual acceptor site located 5′ to exon 6. This mutation further causes an in-frame 15 amino acid (AA) deletion (which includes a cysteine) which most likely effects the folding of the resultant protein. Studies to investigate and assess the novel splice adaptor site and the effects of the 15 AA deletion on FAS expression and on in vitro apoptosis are currently in progress.