JAK3 mutations in Italian patients affected by SCID: New molecular aspects of a long‐known gene

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.

Clinical, Immunological, and Molecular Features of Typical and Atypical Severe Combined Immunodeficiency: Report of the Italian Primary Immunodeficiency Network

“…As for the two JAK3- mutated patients, they carried previously described hypomorphic mutations (46, 51). Functional immunological and genetic studies are mandatory to recognize such patients, since most of these patients had near normal total CD4 and/or CD8 counts.…”

Human adenosine deaminase 2 deficiency: A multi‐faceted inborn error of immunity

“…Copy number variations (CNVs) are numerous across the gene locus. ALU‐mediated deletion is a common mechanism for the formation of CNVs in the human genome, including in primary immunodeficiency disease (PID) related genes . Both ADA1 and ADA2 also have a low gene damage index Phred score, of 5.607 and 6.29, respectively, which is well below the cut‐off GDI = 13.84, based on the distribution of all disease‐causing human genes .…”

Mutations in JAK/STAT and NOTCH1 Genes Are Enriched in Post-Transplant Lymphoproliferative Disorders

“…The JAK/STAT pathway plays an important role in the regulation of cell proliferation and immune system response, especially by involvement of cytokine and interleukin signaling ( 28 ). JAK3 mutations have been reported in mainly T-cell neoplasms ( 29 ,) ( 30 ), immunodeficiency syndromes ( 31 , 32 ), and B-cell neoplasms ( 33 ). The mutations found in our PTLD and FFH cases fall into the SH2 and JH2 domains of the JAK3 gene.…”