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Research shows that six different mutations in the hMunc13-4, a member of the Munc13 family of proteins, indicate that the gene is not required for granule polarization and membrane docking. However, it is essential for the secretion of cytotoxic granules during exocytosis. Together, results implicate HMunc13-4 mutations in the development of FHL3.

Severe combined immunodeficiency-X1 (SCID-X1) is an X-linked inherited disorder characterized by an early block in T and natural kilter (NK) lymphocyte differentiation. This block is caused by mutations of the gene encoding the [Gamma]c cytokine receptor subunit of interteukin-2, -4, -7, -9, and -15 receptors, which participates in the delivery of growth, survival, and differentiation signals to early lymphoid progenitors. After preclinical studies, a gene therapy trial for SCID-X1 was initiated, based on the use of complementary DNA containing a defective [Gamma]c Moloney retrovirus-derived vector and ex vivo infection of [CD34.sup.+] cells. After a 10-month follow-up period, [Gamma]c transgene-expressing T and NK cells were detected in two patients. T, B, and NK cell counts and function, including antigen-specific responses, were comparable to those of age-matched controls. Thus, gene therapy was able to provide full correction of disease phenotype and, hence, clinical benefit., In considering diseases that might be ameliorated by gene therapy, a setting in which a selective advantage is conferred by transgene expression, in association with long-lived transduced cells such as [...]

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare, rapidly fatal, autosomal recessive immune disorder characterized by uncontrolled activation of T cells and macrophages and overproduction of inflammatory cytokines. Linkage analyses indicate that FHL is genetically heterogeneous and linked to 9q21.3-22, 10q21-22, or another as yet undefined locus. Sequencing of the coding regions of the perforin gene of eight unrelated 10q21-22-linked FHL patients revealed homozygous nonsense mutations in four patients and missense mutations in the other four patients. Cultured lymphocytes from patients had defective cytotoxic activity, and immunostaining revealed little or no perforin in the granules. Thus, defects in perforin are responsible for 10q21-22-[inked FHL Perforin-based effector systems are, therefore, involved not only in the lysis of abnormal cells but also in the down-regulation of cellular immune activation., FHL is a hemophagocytic lymphohistiocytic disorder in which previously healthy young children present with fever, splenomegaly, hepatomegaly, pancytopenia, coagulation abnormalities, neurological abnormalities, and high serum concentrations of interferon-[Gamma] (IFN-[Gamma]) and [...]