Signaling lymphocytic activation molecule(SLAM)-associated protein(SAP)is a Src homology(SH)domain 2-containing intracellular adaptor protein that is predominantly expressed in the hematopoietic system by T lymphocytes and NK cells.SAP protein is encoded by the SH2D1A gene located on the X chromosome.Loss-of-function mutations in SAP cause the X-linked lymphoproliferative disease(XLP),a severe immunodeficiency characterized by heightened susceptibility to Epstein-Barr virus and impaired humoral immunity.Normal individuals express several functional and non-functional isoforms of SAP as a result of alternative splicing.In this study,we identify a cryptic exon in the murine Sh2d1a gene.At the mRNA level,the new isoform of SAP(SAP-2)that includes this new exon is widely expressed in lymphoid tissues by C57BL/6 and 129 strains of inbred mice.SAP-2 accounts for approximately 1%3%of total SAP transcripts,and it is dynamically regulated during lymphocyte activation.At the protein level,the SAP-2 isoform is a 144 amino-acid protein.Compared to the dominant 126 amino-acid SAP-1 isoform,the additional 18 amino acids are inserted into a structural region that is critical for phosphotyrosine binding.Our functional analysis in vitro indicates that SAP-2 is a non-functional isoform due to decreased protein stability.Thus,both human and mouse have multiple SAP splice isoforms that may or may not function.Modulation of relative proportions of these isoforms is potentially a mechanism whereby cells can regulate SAP-mediated biological activities. Signaling lymphocytic activation molecule (SAP) is a Src homology (SH) domain 2-containing intracellular adapter protein that is predominantly expressed in the hematopoietic system by T lymphocytes and NK cells. SAP protein is encoded by the SH2D1A gene located on the X chromosome. Loss-of-function mutations in SAP cause the X-linked lymphoproliferative disease (XLP), a severe immunodeficiency characterized by heighten susceptibility to Epstein-Barr virus and impaired humoral immunity. Normal individuals express several functional and non- functional isoforms of SAP as a result of alternative splicing. In this study, we identify a cryptic exon in the murine Sh2d1a gene. At the mRNA level, the new isoform of SAP (SAP-2) that includes this new exon is widely expressed in lymphoid tissues by C57BL / 6 and 129 strains of inbred mice. SAP-2 accounts for approximately 1% 3% of total SAP transcripts, and it is dynamically regulated during lymphocyte activation. At the protein level, the SA P-2 isoform is a 144 amino-acid protein .Compared to the dominant 126 amino-acid SAP-1 isoform, the additional 18 amino acids are inserted into a structural region that is critical for phosphotyrosine binding. Our functional analysis in vitro said that SAP-2 is a non-functional isoform due to decreased protein stability. Both human and mouse have multiple SAP splice isoforms that may or may not function. Modulation of relative proportions of these isoforms is potentially a mechanism capable of cells capable of regulating SAP- mediated biological activities.