Mutations in the Sterile alpha motif domain containing 9 (SAMD9) gene have been described in patients with severe multisystem disorder, MIRAGE syndrome, but also in patients with bone marrow (BM) failure in the absence of other systemic symptoms. The role of hematopoietic stem cell transplantation (HSCT) in the management of the disease is still unclear. Here, we present a patient with a novel mutation in SAMD9 (c.2471 G>A, p.R824Q), manifesting with prominent gastrointestinal tract involvement and immunodeficiency, but without any sign of adrenal insufficiency typical for MIRAGE syndrome. He suffered from severe CMV (cytomegalovirus) infection at 3 months of age, with a delayed development of T lymphocyte functional response against CMV, profound T cell activation, significantly reduced B lymphocyte counts and impaired lymphocyte proliferative response. Cultured T cells displayed slightly lower calcium flux and decreased survival. At the age of 6 months, he developed severe neutropenia requiring G-CSF administration, and despite only mild morphological and immunophenotypical disturbances in the BM, 78% of the BM cells showed monosomy 7 at the age of 18 months. Surprisingly, T cell proliferation after CD3 stimulation and apoptosis of the cells normalized during the follow-up, possibly reflecting the gradual development of monosomy 7. Among other prominent symptoms, he had difficulty swallowing, requiring percutaneous endoscopic gastrostomy (PEG), frequent gastrointestinal infections, and perianal erosions. He suffered from repeated infections and periodic recurring fevers with the elevation of inflammatory markers. At 26 months of age, he underwent HSCT that significantly improved hematological and immunological laboratory parameters. Nevertheless, he continued to suffer from other conditions, and subsequently, he died at day 440 post-transplant due to sepsis. Pathogenicity of this novel SAMD9 mutation was confirmed experimentally. Expression of mutant SAMD9 caused a significant decrease in proliferation and increase in cell death of the transfected cells. Conclusion: We describe a novel SAMD9 mutation in a patient with prominent gastrointestinal and immunological symptoms but without adrenal hypoplasia. Thus, SAMD9 mutations should be considered as cause of enteropathy in pediatric patients. The insufficient therapeutic outcome of transplantation further questions the role of HSCT in the management of patients with SAMD9 mutations and multisystem involvement.

• Keywords
• MIRAGE, SAMD9, cytomegalovirus infection, dysphagia, gastrointestinal disorder, hematopoietic stem cell transplantation, immunodeficiency, neutropenia,
• MeSH
• Cytomegalovirus Infections genetics   immunology   MeSH
• Infant MeSH
• Humans MeSH
• Mutation MeSH
• Neutropenia genetics   MeSH
• Child, Preschool MeSH
• Smad8 Protein genetics   MeSH
• Immunologic Deficiency Syndromes genetics   MeSH
• Check Tag
• Infant MeSH
• Humans MeSH
• Male MeSH
• Child, Preschool MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Smad8 Protein MeSH
• SMAD9 protein, human MeSH Browser

The T-lymphocyte co-receptors of MHC glycoproteins CD4 and CD8 are known to be associated with the protein tyrosine kinase Lck via cysteine-containing sequences in the cytoplasmic domains of CD4 and CD8 and in the N-terminal domain of Lck. Here we demonstrate that a fraction of CD4 and CD8 molecules are associated with very large, detergent-resistant complexes containing several glycosylphosphatidylinositol-anchored proteins, (glyco)lipids, and protein tyrosine kinases Lck and Fyn but apparently no other major transmembrane proteins. Association of Lck and Fyn with these large complexes is, in contrast to simple CD4/CD8-Lck complexes, not sensitive to alkylation with iodoacetamide. These large complexes therefore represent an alternative way of association of CD4 and CD8 with the protein tyrosine kinases, which may play a role in signaling through these receptors.

• MeSH
• CD4 Antigens analysis   MeSH
• CD8 Antigens analysis   MeSH
• Cell Membrane chemistry   MeSH
• Glycosylphosphatidylinositols MeSH
• Humans MeSH
• Lymphocytes chemistry   MeSH
• Neoplasm Proteins * MeSH
• Lymphocyte Specific Protein Tyrosine Kinase p56(lck) MeSH
• Protein-Tyrosine Kinases analysis   classification   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• CD4 Antigens MeSH
• CD8 Antigens MeSH
• FRK protein, human MeSH Browser
• Glycosylphosphatidylinositols MeSH
• Neoplasm Proteins * MeSH
• Lymphocyte Specific Protein Tyrosine Kinase p56(lck) MeSH
• Protein-Tyrosine Kinases MeSH

The glycosyl phosphatidylinositol (GPI)-linked antigen recognized by monoclonal antibody (mAb) MEM-102 is expressed on all peripheral blood lymphocytes, both resting and activated. Its properties are very similar to a previously described activation antigen, Blast-1. The amino acid sequence deduced from the structure of cloned cDNA is identical to that of the Blast-1 antigen except for a single amino acid residue. There are several other minor differences in the nucleotide sequence of the Blast-1 and MEM-102 cDNAs that do not affect the predicted structure of the polypeptide product. The amino acid sequence of the first 15 N-terminal residues of the antigen purified from Raji cells is found in the deduced sequence close to the presumed boundary between the leader peptide and mature polypeptide. Properties of the recombinant product expressed in COS cells are similar to the antigen isolated from peripheral blood mononuclear cells (PBMNCs) or B-and T-cells lines. The antigen purified on immobilized mAb MEM-102 is recognized by all six known CD48 mAbs under western blotting conditions. COS cells transfected with MEM-102 cDNA react with all the CD48 mAbs. It is concluded that mAb MEM-102 is directed against the as yet poorly characterized antigen CD48, which is therefore structurally closely related to Blast-1. Several possibilities are discussed that might account for the apparent discrepancy between the broad pan-leucocyte expression of the between the broad pan-leucocyte expression of the MEM-102/CD48 antigen and much more restricted expression of the epitope recognized by the previously described mAb defining the Blast-1 antigen.

• MeSH
• CD48 Antigen MeSH
• Antigens, Surface chemistry   MeSH
• Antigens, CD chemistry   MeSH
• Antigens, Differentiation chemistry   MeSH
• Cloning, Molecular MeSH
• Leukocytes, Mononuclear immunology   MeSH
• Humans MeSH
• Membrane Glycoproteins chemistry   MeSH
• Molecular Sequence Data MeSH
• Antibodies, Monoclonal MeSH
• Amino Acid Sequence MeSH
• Base Sequence MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• CD48 Antigen MeSH
• Antigens, Surface MeSH
• Antigens, CD MeSH
• CD48 protein, human MeSH Browser
• Antigens, Differentiation MeSH
• Membrane Glycoproteins MeSH
• Antibodies, Monoclonal MeSH

• MeSH
• Leukocyte Common Antigens MeSH
• Antigens, Differentiation immunology   MeSH
• Epitopes MeSH
• Histocompatibility Antigens immunology   MeSH
• Sialic Acids immunology   MeSH
• Leukocytes immunology   MeSH
• Humans MeSH
• Molecular Weight MeSH
• Antibodies, Monoclonal immunology   MeSH
• Neuraminidase metabolism   MeSH
• Flow Cytometry MeSH
• Antibody Specificity MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Leukocyte Common Antigens MeSH
• Antigens, Differentiation MeSH
• Epitopes MeSH
• Histocompatibility Antigens MeSH
• Sialic Acids MeSH
• Antibodies, Monoclonal MeSH
• Neuraminidase MeSH

• MeSH
• Chromatography, Affinity MeSH
• Antigens, Differentiation immunology   isolation & purification   MeSH
• Humans MeSH
• Membrane Glycoproteins immunology   isolation & purification   MeSH
• Antibodies, Monoclonal MeSH
• Receptors, Immunologic immunology   isolation & purification   MeSH
• Receptors, Lymphocyte Homing MeSH
• T-Lymphocytes analysis   immunology   metabolism   MeSH
• Blotting, Western MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Antigens, Differentiation MeSH
• Membrane Glycoproteins MeSH
• Antibodies, Monoclonal MeSH
• Receptors, Immunologic MeSH
• Receptors, Lymphocyte Homing MeSH