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Intronic SH2D1A mutation with impaired SAP expression and agammaglobulinemia.

ABSTRACT: X-linked lymphoproliferative (XLP) disease is a primary immunodeficiency syndrome associated with the inability to control Epstein-Barr virus (EBV), lymphoma, and hypogammaglobulinemia. XLP is caused by mutations in the SH2D1A gene, which encodes the SLAM-associated protein (SAP), or in the BIRC4 gene, which encodes the X-linked inhibitor of apoptosis protein (XIAP). Here we report a patient with recurrent respiratory tract infections and early onset agammaglobulinemia who carried a unique disease-causing intronic loss-of-function mutation in SH2D1A. The intronic mutation affected SH2D1A gene transcription but not mRNA splicing, and led to markedly reduced level of SAP protein. Despite undetectable serum immunoglobulins, the patient's B cells replicated and differentiated into antibody producing cells normally in vitro.

SUBMITTER: Recher M

PROVIDER: S-EPMC3742382 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Intronic SH2D1A mutation with impaired SAP expression and agammaglobulinemia.

Recher Mike M Fried Ari J AJ Massaad Michel J MJ Kim Hye Young HY Rizzini Michela M Frugoni Francesco F Walter Jolan E JE Mathew Divij D Eibel Hermann H Hess Christoph C Giliani Silvia S Umetsu Dale T DT Notarangelo Luigi D LD Geha Raif S RS

Clinical immunology (Orlando, Fla.) 20121207 2

X-linked lymphoproliferative (XLP) disease is a primary immunodeficiency syndrome associated with the inability to control Epstein-Barr virus (EBV), lymphoma, and hypogammaglobulinemia. XLP is caused by mutations in the SH2D1A gene, which encodes the SLAM-associated protein (SAP), or in the BIRC4 gene, which encodes the X-linked inhibitor of apoptosis protein (XIAP). Here we report a patient with recurrent respiratory tract infections and early onset agammaglobulinemia who carried a unique disea ...[more]

PMID: 23280491

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Project description:Background:X-linked agammaglobulinemia (XLA) is a primary immunodeficiency caused by Bruton's tyrosine kinase (BTK) mutation. Patients are susceptible to severe enterovirus infections. The underlying mechanism remains unknown. BTK is involved in toll-like receptors pathway, which initiates antiviral responses including interferon (IFN) productions. Objective:To demonstrate type I and III IFN productions in dendritic cells of XLA patients is decreased in response to oral poliovirus vaccine (OPV) but not H1N1 virus. Methods:Monocyte-derived dendritic cells (MoDCs) were derived from nine XLA patients aged 22-32?years old and 23 buffy coats from Hong Kong Red Cross blood donors. LFM-A13 was used to inhibit BTK. OPV Sabin type 1 and H1N1 influenza virus were used to stimulate MoDCs with RPMI as mock stimulation. The antiviral cytokine productions and phenotypic maturation of MoDCs were determined 24?h post-stimulation. OPV RNA was determined at 0, 6, 12, and 24?h post-stimulation. Results:Upon OPV stimulation, IFN-?2, IFN-?, and IFN-?1 productions in MoDCs from XLA patients and BTK-inhibited MoDCs of healthy controls were significantly lower than that from healthy controls. Whereas upon H1N1 stimulation, the IFN-?2, IFN-?, and IFN-?1 productions were similar in MoDCs from XLA patients, BTK-inhibited MoDCs of healthy controls and healthy controls. The mean fluorescent intensities (MFI) of CD83, CD86, and MHC-II in MoDCs from XLA patients in response to OPV was similar to that in response to mock stimulation, while the MFI of CD83, CD86, and MHC-II were significantly higher in response to H1N1 stimulation than that in response to mock stimulation. Whereas, the MFI of CD83, CD86, and MHC-II in MoDCs of healthy controls were significantly higher in response to both OPV and H1N1 stimulation compared to that in response to mock stimulation. Conclusion:Production of type I and III IFN in response to OPV was deficient in MoDCs from XLA patients, but was normal in response to H1N1 due to deficient BTK function. Moreover, phenotypic maturation of MoDCs from XLA patients was impaired in response to OPV but not to H1N1. These selective impairments may account for the unique susceptibility of XLA patients toward severe enterovirus infections.

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Intronic SH2D1A mutation with impaired SAP expression and agammaglobulinemia.

Publications

Intronic SH2D1A mutation with impaired SAP expression and agammaglobulinemia.

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