Abstract
BackgroundMutations in the Janus Kinase 3 (JAK3) gene cause an autosomal recessive form of severe combined immunodeficiency (SCID) usually characterized by the absence of both T and NK cells, but preserved numbers of B lymphocytes (T‐B+NK‐SCID). The detection of larger (>100 bp) genomic duplications or deletions can be more difficult to be detected by PCR‐based methods or standard NGS protocols, and a broad range of mutation detection techniques are necessary.MethodsWe report four unrelated Italian patients (two females and two males) with SCID phenotype. Protein expression, functional studies, molecular analysis by standard methods and NGS, and transcripts studies were performed to obtain a definitive diagnosis.ResultsHere, we describe four JAK3‐deficient patients from four unrelated families. The first patient is homozygous for the known c.1951 C>T mutation causing the amino acidic change p.R651W. The other two patients, originating from the same small Italian town, resulted compound heterozygotes for the same g.15410_16542del deletion and two different novel mutations, g.13319_13321delTTC and c.933T>G (p.F292V), respectively. The fourth patient was compound heterozygous for the novel mutations p.V599G and p.W709R. Defective STAT5 phosphorylation after IL2 or IL15 stimulation corroborated the mutation pathogenicity. Concerning g.15410_16542del mutation, probably due to an unequal homologous recombination between Alu elements of JAK3 gene, microsatellites analysis revealed that both unrelated Pt2 and Pt3 and their carrier family members shared the same haplotype. These data support the hypothesis of a founder effect for the g.15410_16542del mutation that might have inherited in both unrelated families from the same ancient progenitor.ConclusionDifferent molecular techniques are still required to obtain a definitive diagnosis of AR‐SCID particularly in all cases in which a monoallelic mutation is found by standard mutation scanning methods.
Highlights
Severe combined immunodeficiency (SCID) is a heterogeneous group of primary immunodeficiency disorders characterized by defect of both T and B lymphocyte development and function (Buckley, 2000; O’Shea et al, 2004)
Janus Kinase 3 (JAK3) has a key role in the signaling downstream of the common gamma-chain subunit that is an essential component of the IL-2, IL-4, IL-7, IL-9, IL15, and IL-21 receptor complexes; JAK3-deficiency is the main cause of T-B+NK- AR-severe combined immunodeficiency (SCID) (OMIM: #600802; Wu & Sun, 2011; Rochman, Spolski, & Leonard, 2009)
In Patient 1 (Pt1), JAK3 protein investigation, performed on EBV-B cells, showed a reduced protein expression compared with HD (Figure 1)
Summary
Severe combined immunodeficiency (SCID) is a heterogeneous group of primary immunodeficiency disorders characterized by defect of both T and B lymphocyte development and function (Buckley, 2000; O’Shea et al, 2004). The X-linked SCID (X-SCID), caused by mutations in IL2RG gene encoding the common gamma-chain (c-chain), is the most frequent form of the disease and its clinical phenotype is comparable to that of autosomal recessive SCID (ARSCID) caused by Janus kinase 3 (JAK3) gene mutations (OMIM: * 600173). The most frequent defect resulted in a marked reduction or complete absence of the JAK3 protein expression/function, patients with missense mutations and a reduced JAK3 functional activity could show an atypical and less severe immunological phenotype (Frucht et al, 2001; Scarselli et al, 2016). The g.15410_16542del, we suggest a mechanism of recombination between Alu elements as cause of deletion. This mutation was found in two unrelated patients and a possible founder effect was investigated. Protein and molecular studies were performed to have a definitive diagnosis in these patients
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