The genetic and biochemical basis of Omenn syndrome

Citation
S. Santagata et al., The genetic and biochemical basis of Omenn syndrome, IMMUNOL REV, 178, 2000, pp. 64-74
Citations number
119
Language
INGLESE
art.tipo
Review
Categorie Soggetti
Immunology
Journal title
IMMUNOLOGICAL REVIEWS
ISSN journal
0105-2896 → ACNP
Volume
178
Year of publication
2000
Pages
64 - 74
Database
ISI
SICI code
0105-2896(200012)178:<64:TGABBO>2.0.ZU;2-#
Abstract
Omenn syndrome (OS) is a peculiar, autosomal recessive severe combined immu nodeficiency (SCID) associated with early-onset, generalized, exudative ery throdermia; lymphoadenopathy; hepato- and splenomegaly; hypereosinophilia; elevated serum IgE; and normal to high activated, yet non-functional oligoc lonal T cells. Recent investigations have shown that the primum movens of a ll these puzzling features lies in a defect of the lymphoid-specific V(D)J recombination process. Abnormalities in both alleles of either Rag-1 or -2 genes are found in all OS patients. At variance with T-B- SCID, whose Rag m utations represent null alleles, OS mutations maintain a residual recombina tion activity, allowing limited T-cell receptor gene rearrangements to occu r in the thymus. The gene rearrangements are subsequently expanded in the p eriphery after environmental antigen exposure. Missense mutations detected in OS have been examined in a number of biochemical assays and have contrib uted to dissect the various functional domains of both Rag-1 and Rag-2 prot eins. The examination of a set of mutations occurring in the Rag-1 N-termin al portion has demonstrated that this region plays a fundamental role in vi vo. The elucidation of the molecular basis of OS has allowed us to perform early prenatal diagnosis and could be the basis for trials of in utero bone marrow transplantation or gene therapy approaches.