Disseminated cryptococcal infection in patient with novel JAK3 mutation severe combined immunodeficiency, with resolution after stem cell transplantation.
Our results indicate that the novel R776W missense mutation in RAG-1 is causal in the T(-)B(-)NK(+) SCID phenotype in Athabascan-speaking Dine Indians from the Canadian Northwest Territories.
Here we describe a naturally occurring Jak3 mutation from a patient with autosomal severe combined immunodeficiency (SCID), where a single amino acid substitution, Y100C, in Janus homology domain 7 (JH7) prevents kinase-receptor interaction.
In humans, most T(-)B(-) severe combined immunodeficiencies (SCID) have a defect in either the RAG1 or RAG2 gene, are not radiosensitive and do not show genome instability.
We have studied a mut/mut mouse model of leaky SCID with a homozygous Rag1S723C mutation that impairs, but does not abrogate, V(D)J recombination activity.
Mutations in Janus kinase 3 (JAK3) are a cause of severe combined immunodeficiency, but hypomorphic JAK3 defects can result in a milder clinical phenotype, with residual development and function of autologous T cells.
Both patients had the same JAK3 gene mutation, suggesting that maternal engraftment may result in immune competence leading to long-term survival in patients with severe combined immune deficiency.
While the inactivation mutations that eliminate JAK3 function lead to the immunological disorders such as severe combined immunodeficiency, activation mutations, causing constitutive JAK3 signaling, are known to trigger various types of cancer or are responsible for autoimmune diseases, such as rheumatoid arthritis, psoriasis, or inflammatory bowel diseases.
Here, we use zinc-finger nucleases to generate rats that lack either the Prkdc gene (SCID) or the Prkdc and Il2rg genes (referred to as F344-scid gamma [FSG] rats).
We evaluated long-term clinical features, longitudinal immunoreconstitution, donor chimerism, and quality of life (QoL) of IL2RG/JAK3SCID patients >2 years post-HSCT at our center.
In vitro experiments in DNA-dependent protein kinase catalytic subunitsevere combined immunodeficiency (Prkdc scid) fibroblasts using designed zinc finger nucleases (ZFN) and a repair template demonstrated molecular and functional correction of the defect.
Amorphic mutations in RAG1 and RAG2 cause T(-)B(-)NK(+)SCID, whereas hypomorphic mutations cause an immunodeficency characterized by oligoclonal expansion of TCRgammadelta T cells, severe CMV infection and autoimmunity.
In XSCID and SCID resulting from mutations in JAK3, which encodes a Janus family tyrosine kinase that couples to gamma(c) and is required for gamma(c)-dependent signalling, T- and natural killer (NK)-cells are decreased but B-cell numbers are normal (T(-)B(+)NK(-)SCID).
We have recently experienced a rare case of OS showing the revertant mosaicism due to multiple second-site mutations leading to typical OS clinical features with RAG1-deficient SCID.
The immunophenotypic and immunogenotypic B-cell differentiation arrest in bone marrow of RAG-deficient SCID patients corresponds to residual recombination activities of mutated RAG proteins.