Identical mutations in RAG1 or RAG2 genes leading to defective V(D)J recombinase activity can cause either T-B-severe combined immune deficiency or Omenn syndrome.
The patient carrying this 631delTRAG1 gene mutation died at the age of 5 weeks from an Omenn syndrome-like T(+)/B(- )severe combined immunodeficiency disease.
Mutations of the Janus kinase 3 (JAK3) have been previously described to cause an autosomal recessive variant of severe combined immunodeficiency (SCID) usually characterized by the near absence of T and NK cells, but preserved numbers of B lymphocytes (T-B+SCID).
Two recessive RAG-1 mutations responsible for B-cell-negative SCID, R621H and E719K, impair V(D)J recombination without affecting formation of single-site recombination signal sequence complexes, specific DNA contacts, or perturbation of DNA structure at the heptamer-coding junction.
Janus kinase 3 (JAK3) tyrosine kinase has a central role in the control of lymphopoiesis, and mutations in JAK3 can lead to either severe combined immunodeficiency or leukemia and lymphomas.
Our data show that mutation c.256_257delAA in RAG1 gene seems to occur quite frequently in the polish patients with severe combined immunodeficiency and may result in classical OS as well as in severe combined immunodeficiency without clinical and laboratory features of OS when occurred in homozygous state.
The most popular mouse strains used in research, the NOG (NOD.Cg-Prkdc<sup>scid</sup> Il2rγ<sup>tm1Sug</sup>/Jic) and the NSG (NOD/SCID-IL2Rγ<sup>-/-</sup>, NOD.Cg-Prkdc<sup>scid</sup>Il2rγ<sup>tm1Wjl</sup>/SzJ) mouse, and their human-cytokine-producing (interleukin-3, granulocyte-macrophage colony-stimulating factor, and stem cell factor) counterparts (huNOG and NSGS), rely partly on a mutation in the DNA repair protein PRKDC, causing a severe combined immune deficiency (SCID) phenotype and rendering the mice less tolerant to DNA-damaging therapeutics, thereby limiting their usefulness in the investigation of novel acute myeloid leukemia (AML) therapeutics.
A human SCID condition is also characterized by an absence of mature T and B lymphocytes and is associated with mutations in either RAG1- or RAG2-encoding genes.
The use of HLA-identical hematopoietic stem cell transplantation (HSCT) demonstrates overall survival rates greater than 75 % for T-B-NK+ severe combined immunodeficiency secondary to pathogenic mutation of recombinase activating genes 1 and 2 (RAG1/2).
It has been recently shown that mutations in both of the recombination activating genes RAG1 and RAG2 are involved in each of the two different types of severe combined immunodeficiency (SCID) syndromes: T-B- SCID and Omenn's syndrome (OS).
These presentations are consistent with atypical severe combined immunodeficiency (SCID)/Omenn Syndrome and the diagnosis was confirmed by demonstration of homozygosity for the R841W mutation in the catalytic core of RAG1.
A striking phenotype associated with inactivating Jak3 mutations is severe combined immunodeficiency syndrome, whereas mutation of Tyk2 results in another primary immunodeficiency termed autosomal recessive hyperimmunoglobulin E syndrome.
In this study we describe three patients with a novel deep intronic mis-splicing mutation in JAK3 as a cause of T-B+NK- SCID highlighting the need for careful evaluation of intronic regulatory elements of known genes associated with clearly defined clinical phenotypes.