Severe Combined Immunodeficiency Caused by Defects in VDJ Recombination and PreTCR Checkpoint Signaling

Absence of V(D)J recombination leads to a failure to express the pre-TCR and the pre-BCR and a block in T and B cell development. Mutations in the RAG1 or RAG2 genes (whose protein products mediate the cleavage step during V(D)J recombination) or the ARTEMIS gene, which encodes an endonuclease that resolves coding-end hairpins during V(D)J recombination, all result in a failure of V(D)J recombination. These diseases are rare, but they account for a large number of the autosomal recessive forms of SCID. The normal functions of these genes are discussed in Chapter 8. In children with these mutations, B and T lymphocytes are absent and immunity is severely compromised. Mutations in genes encoding proteins involved in double-stranded break repair/ nonhomologous end joining of DNA also lead to SCID because of defects in V(D)J recombination. Homozygous mutations in the gene encoding the catalytic subunit of the DNA-dependent protein kinase (DNA-PK), CERNUNNOS/XLF, and DNA LIGASE 4 all lead to SCID. Among the many functions of DNA-PK is the phosphory-lation and activation of ARTEMIS, and CERNUNNOS interacts with the XRCC4/DNA ligase 4 complex and presumably facilitates the ligation event that completes the nonhomologous end-joining process. Genetic defects in this end-joining process also result in increased cellular sensitivity to radiation and can result in other manifestations, such as microcephaly, facial dysmorphisms, and defective tooth development.

Hypomorphic mutations (that only partially reduce function) in the RAG genes, in ARTEMIS, or in the IL7RA gene are the cause of a disorder characterized by restricted generation of T and B cells, immunodeficiency, and immune dysregulation. This disorder is known as Omenn's syndrome. It is phenotypically different from the diseases described above because in this disease immunodeficiency coexists with exaggerated immune activation and autoimmunity. This may be caused by relative absence of regulatory T cells, or in cases with decreased V(D)J recombination, defective receptor editing in immature B cells.

Although most autosomal recessive forms of SCID are linked to mutations in ADA, RAG1, RAG2, and ARTEMIS, rare forms of this syndrome are caused by mutations in the genes encoding the CD45 phosphatase (that is a positive regulator of Src family kinases, such as Fyn, Lck, and Lyn) and mutations in the CD3 8 or e chains or in the CD3-associated Z chain. These mutations contribute to defective pre-TCR signaling and result in a block in aP T cell development.

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