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An immunocompetent patient with a nonsense mutation in NHEJ1 gene
Hossein Esmaeilzadeh1,2, Mohammad Reza Bordbar3, Zahra Hojaji2
1Allergy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
Background:
DNA double-strand breaks (DSBs) are among the most deleterious types of DNA damage. DSBs are repaired by homologous recombination or non-homologous end-joining (NHEJ). NHEJ, which is central to the process of V(D)J recombination is the principle pathway for DSB repair in higher eukaryotes. Mutations in NHEJ1 gene have been associated with severe combined immunodeficiency.
Case Presentation:
The patient was a 3.5-year-old girl, a product of consanguineous first-degree cousin marriage, who was homozygous for a nonsense mutation in NHEJ1 gene. She had initially presented with failure to thrive, proportional microcephaly as well as autoimmune hemolytic anemia (AIHA), which responded well to treatment with prednisolone. However, the patient was immunocompetent despite having this pathogenic mutation.
Conclusions:
Herein, we report on a patient who was clinically immunocompetent despite having a pathogenic mutation in NHEJ1 gene. Our findings provided evidence for the importance of other end-joining auxiliary pathways that would function in maintaining genetic stability. Clinicians should therefore be aware that pathogenic mutations in NHEJ pathway are not necessarily associated with clinical immunodeficiency.
Insights
A pathogenic mutation in the NHEJ1 gene, typically linked to immunodeficiency, did not cause clinical immune deficiency in one patient. This highlights the role of alternative DNA repair pathways in maintaining genetic stability.
Area of Science:
- Genetics
- Immunology
- Molecular Biology
Background:
- DNA double-strand breaks (DSBs) are critical DNA lesions repaired by homologous recombination or non-homologous end-joining (NHEJ).
- NHEJ is crucial for V(D)J recombination and is the primary DSB repair pathway in higher eukaryotes.
- Mutations in the NHEJ1 gene are often associated with severe combined immunodeficiency (SCID).
Observation:
- A 3.5-year-old girl, homozygous for a nonsense mutation in NHEJ1, presented with failure to thrive, microcephaly, and autoimmune hemolytic anemia.
- The patient's autoimmune hemolytic anemia responded to prednisolone treatment.
- Despite the pathogenic NHEJ1 mutation, the patient remained clinically immunocompetent.
Findings:
- This case report details a patient with a pathogenic NHEJ1 mutation who did not exhibit clinical immunodeficiency.
- The findings suggest the involvement of alternative end-joining pathways in compensating for NHEJ1 defects.
- Genetic stability was maintained despite the presence of a mutation in a key DNA repair gene.
Implications:
- Pathogenic mutations in the NHEJ pathway are not always indicative of clinical immunodeficiency.
- Alternative DNA repair mechanisms can compensate for defects in canonical NHEJ.
- Clinicians should consider the possibility of immunocompetence in patients with NHEJ pathway mutations.
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