SH2D1A mutation analysis for diagnosis of XLP in typical and atypical patients

X-linked lymphoproliferative syndrome (XLP) is a rare, often fatal, primary immunodeficiency disease characterized by an abnormal response to Epstein-Barr virus (EBV) infection. The gene responsible for XLP has been identified as SH2D1A/DSHP/SLAMassociated protein (SAP). The major clinical manifestations include fulminant infectious mononucleosis, lymphoproliferative disorder, and dysgammaglobulinemia. Affected males uncommonly present with lymphocytic vasculitis in addition to aplastic anemia. In this study, we describe a Japanese XLP patient who presented with hypogammaglobulinemia following acute EBV-induced infectious mononucleosis in the infancy and later had systemic lymphocytic vasculitis and hemophagocytic lymphohistiocytosis in the adulthood, which resolved by steroid pulse therapy. The patient's SAP gene was found to harbor a missense mutation (His8Asp), presumably resulting in defective expression of SAP in T cells. Biopsy specimens of lung and skin disclosed that CD8 + T cells predominantly infiltrated vascular vessels. However, immunohistochemical examination showed that EBV-infected cells were not identifiable in the vessels. We propose that T-cell-mediated immune dysregulation in XLP can cause vasculitis by EBV infectionunrelated mechanism. Am.

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“…The occurrence of hypogammaglobulinemia after EBV infection has been considered to be suggestive of XLP [2,13].…”

Section: Discussionmentioning

confidence: 99%

X-linked lymphoproliferative syndrome presenting with systemic lymphocytic vasculitis

et al. 2005

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“…[3][4][5]16 The phosphotyrosine binding pocket of the SH2 domain contains 3 positively charged arginine residues (Arg13, Arg 32, and Arg55). Such positively charged residues have been shown to mediate the binding of a ligand in a homologous SH2-containing protein, Abl.…”

Section: Discussionmentioning

confidence: 99%

Lymphocytic vasculitis in X-linked lymphoproliferative disease

Dutz

Benoît

Wang

et al. 2001

Blood

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IntroductionX-linked lymphoproliferative syndrome (XLP) or Duncan disease is a fascinating disease that presents as an Epstein-Barr virus (EBV)-specific immune defect. The original case, described by David Purtilo in 1975 1 involved an 8-year-old boy who died of fulminant hepatitis and bone marrow failure 1 month after the onset of acute infectious mononucleosis (IM). A few years later, it was noted that 2 brothers had also died of illnesses resembling fulminant IM, and it was learned that 3 maternally related male cousins had also died as a result of complications of an EBV infection. Purtilo correctly deduced that a novel X-linked disease was present in this family -a disease that resulted in substantial mortality and morbidity after primary exposure to EBV. By 1978, an XLP registry was established to facilitate the study of the disease, and 3 main clinical presentations were ascribed 2 : (I) fulminant infectious mononucleosis and death, (ii) dysgammaglobulinemia with elevated levels of IgM and IgA and decreased levels of IgG, and (iii) extranodal lymphomas of either B-or T-cell origin. Other less common expressions of the disease have been reported, including aplastic anemia, virus-associated hemophagocytosis (VAHS), and pulmonary vasculitis. Many XLP kindred have been studied extensively in an effort to characterize the nature of the immune defect, leading to a specific susceptibility to EBV. Interest in these cases continues as EBV infection is ubiquitous and has been implicated in the genesis of both lymphoid and mesenchymal tumors. It has been hoped that a better understanding of patients with XLP and their immunologic defects may shed light on the unique nature of the relationship between EBV and human infection.The molecular basis for XLP has recently been ascribed to mutations affecting the SLAM-associated protein (SAP). 3-5 SAP is a Src-homology 2 (SH2) domain-containing protein. Expression of SAP protein has been detected in both murine thymus and human peripheral blood lymphocytes. 3 SAP RNA has been detected primarily in T cells, T-cell lines, and in both T-and B-cell neoplasms. 5 Expression of RNA has been detected in lymphoid germinal centers and natural killer (NK) cells by some 4 but not others. 3 The SAP gene contains 4 exons and encodes a protein of 128 amino acids with a single SH2 domain. This SH2 domain has been shown to interact with the costimulatory surface molecule termed signaling lymphocyte activation molecule (SLAM)/ CDw150 in lymphocytes 3 and the costimulatory molecule 2B4 present in NK cells and some T cells. 6 The binding of SAP to 2B4 or SLAM has been proposed to regulate cell signaling through these molecules. How the described mutations in SAP produce an XLP phenotype is still unclear.We describe a patient who died as a result of chronic systemic vasculitis and fulfilled clinical criteria for the diagnosis of XLP. Sequencing of this patient's SAP gene revealed a novel mutation affecting the SH2 domain. Immunohistochemical analysis using antibodies to CD45RO and CD8 revealed t...

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“…The vast majority of mutations affect exonic sequences; one mutation in intron 3, five mutations in intron 2, and seven mutations in intron 1 have been reported (Fig. 1) [1,10,[14][15][16][17][18][19][20][21].…”

Section: X-linked Lymphoproliferative Disease (Xlp) (Omim #611432)mentioning

confidence: 99%

Severe XLP Phenotype Caused by a Novel Intronic Mutation in the SH2D1A Gene

et al. 2014

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We describe here a novel c.137+5G > A intronic mutation in the SH2D1A gene of the signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) in association with Epstein-Barr virus (EBV)-induced fatal infectious mononucleosis (FIM) in an 8-year-old male patient and his 3-year-old step brother. The mother and the maternal grandmother of the boys are healthy and heterozygous for this sequence variant. Genetic sequencing of blood-cell-derived cDNA in the younger patient revealed a 22 bp deletion in the SH2D1A cDNA. Immunoblot and flow cytometry analysis performed in this younger patient showed the lack of SAP protein expression in peripheral blood lymphocytes. These data suggest that the novel c.137+5G > A mutation results in loss of function of SAP protein and leads to typical Xlinked lymphoproliferative disease phenotype. We propose that intron 1 and the c.137+5G may be the most frequent intronic hot spot for SH2D1A splicing mutation.

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SH2D1A mutation analysis for diagnosis of XLP in typical and atypical patients

Cited by 34 publications

References 19 publications

X-linked lymphoproliferative syndrome presenting with systemic lymphocytic vasculitis

X-linked lymphoproliferative syndrome presenting with systemic lymphocytic vasculitis

Lymphocytic vasculitis in X-linked lymphoproliferative disease

Severe XLP Phenotype Caused by a Novel Intronic Mutation in the SH2D1A Gene

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