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A novel CTLA-4 deletion variant in a child with refractory autoimmune hemolytic anemia: molecular and functional
Feng Chen1, Siyu Lei1,2, Caihui Yuan3
1Department of Hematology, Jiangxi Provincial Children's Hospital, Nanchang, China.
Insights
A novel cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) deletion variant was identified in a child with refractory autoimmune hemolytic anemia (AIHA). This discovery suggests CTLA-4 deficiency as a potential cause of pediatric AIHA, requiring further investigation.
Area of Science:
- Immunology
- Genetics
Background:
- Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a critical immune checkpoint.
- CTLA-4 deficiency is a known cause of inborn errors of immunity.
Purpose of the Study:
- To characterize a novel CTLA-4 deletion variant in a pediatric patient with refractory autoimmune hemolytic anemia (AIHA).
- To delineate the clinical profile and elucidate the pathogenic mechanism of the identified CTLA-4 variant.
Main Methods:
- Trio-based whole-exome sequencing (WES) was performed.
- Candidate variants were validated using Sanger sequencing.
- In vitro functional assays (qPCR, Western blot) assessed mRNA and protein expression.
Main Results:
- A novel CTLA-4 deletion variant (c.362_391del) was identified in the immunoglobulin V-set domain.
- In vitro experiments showed significantly reduced mRNA and protein expression levels due to the variant.
Conclusions:
- The CTLA-4 (c.362_391del) variant may contribute to refractory AIHA in children.
- CTLA-4 variants should be considered in the differential diagnosis of pediatric AIHA, especially in refractory cases.
Objective:
As a critical immune checkpoint, cytotoxic T-lymphocyte-associated protein 4(CTLA-4)deficiency is a well-established cause of inborn errors of immunity. This study characterizes a novel CTLA-4 deletion variant identified in a pediatric case of refractory autoimmune hemolytic anemia (AIHA), with the aim of delineating the clinical profile and elucidating the underlying pathogenic mechanism.
Methods:
Trio-based whole-exome sequencing (WES) was performed on peripheral blood samples from a 6-year-old female with refractory AIHA and her parents. Candidate variants were validated by Sanger sequencing. Structural modeling of mutant CTLA-4 was conducted, followed by in vitro functional assays in 293T cells to assess mRNA transcription (qPCR) and protein expression (Western blot).
Results:
A CTLA-4 (c.362_391del) variant was identified within the immunoglobulin V-set domain of the CTLA-4 protein. In vitro experiments demonstrated significant reductions in both mRNA and protein expression levels caused by this variant.
Conclusion:
The CTLA-4 (c.362_391del) variant may contribute to refractory AIHA in children. This case highlights the potential necessity of including CTLA-4 variants in the differential diagnosis of pediatric AIHA, particularly when conventional therapies prove ineffective, and warrants further validation in larger cohorts.
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