Germline FAS gene mutation in a case of ALPS and NLP Hodgkin lymphoma

Abstract

FAS germline mutations have been associated with the development of autoimmune lymphoproliferative syndrome (ALPS). Occurrence of Hodgkin lymphoma (HL) has been reported in 2 families with ALPS. In both families an uncle of the index patient developed HL. A 15-year-old boy with autoimmune thrombopenia, lymphadenopathy, and splenomegaly for 6 years was studied. In an axillary lymph node biopsy nodular lymphocyte predominant (NLP) HL was diagnosed; in the areas between the nodules a proliferation of double-negative blastic T cells were present, suggestive of ALPS. Analysis for the presence of a FAS gene mutation using the denaturing gradient gel electrophoresis technique indicated a mutation in exon 9. Direct sequence analysis revealed a mutation causing a substitution of arginine with glutamine at codon 234. Because ALPS and NLP HL are both highly infrequent conditions, the occurrence in at least 3 families suggests a causative relationship between germline FAS gene mutations and NLP HL. (Blood.

Autoimmune lymphoproliferative syndrome in a patient with a new minimal deletion in the death domain of the FAS gene

“…x63717). Codons 1 to 16 represent the signal peptide, and the mature peptide consists of 319 amino acids (17-335) [8]. The same aberrant banding pattern was detected by DGGE in both biopsies (Fig.…”

“…Ten sets of primers were used to amplify all 9 exons of the FAS gene [7,8]. PCR products were denatured for 10 minutes at 94°C, and heteroduplex molecules were formed for 50 minutes at 55°C.…”

“…Since the original clinical description by Canale and Smith [1], followed by the characterization of an abnormal T-cell proliferation with lymphocyte apoptosis defect and the demonstration of FAS gene mutations [2][3][4][5], many cases have been described [6][7][8]. The main features of ALPS are as follows: early childhood onset, prominent nonmalignant lymphadenopathy, hepatosplenomegaly, autoimmune manifestations and blood count alterations such as expanded populations of CD4− CD8− (double-negative T cells) [4,9], and in vitro defects in lymphocytes apoptosis.…”

Lymphocyte predominant Hodgkin’s disease

“…The FAS protein is a member of the tumor necrosis factor receptor family and plays an important role in promoting apoptosis of autoreactive lymphocytes. A recent case report describes the development of LPHD in a patient with an inherited mutation in the FAS gene and lends further support for the role of apoptosis in the development of LPHD [18]. Bcl-6, a Kruppel-type zinc finger protein, is a transcriptional repressor that prevents germinal center B cells from undergoing terminal differentiation.…”

Unique Gene Expression Patterns in Human T‐cell Lines Generated from Multiple Sclerosis Patients by Stimulation with a Synthetic MOG Peptide

“…LFG is known to inhibit T-cell death mediated by the Fas receptor (CD95) through a unique mechanism that down regulates apoptotic signals from Fas (Somia et al 1999). Loss of Fas/Fas ligand activities was reported in human autoimmune lymphoproliferative syndrome (Van den Berg et al 2002), and in lymphoproliferative lupus-like syndrome in mice (Watanabe et al 1992). The MAP3K12 gene is associated with programmed cell death and was reported to catalyze the phosphorylation of BAD, a member of the BCL2 protein family which stimulates BCL2 dependent anti-apoptotic pathways (Yang et al 1995, Bonni et al 1999.…”