Novel Mutations in ACP5 and SAMHD1 in a Patient With Pediatric Systemic Lupus Erythematosus
Soon-Min Hong1,2, Wei Chen3, Jiaqi Feng2
1Shanghai Institute of Rheumatology, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China.
Insights
Genetic analysis of a pediatric systemic lupus erythematosus (pSLE) patient revealed novel mutations in ACP5 and SAMHD1 genes. These alterations impact immune pathways, suggesting a role in pSLE pathogenesis and potential therapeutic targets.
Area of Science:
- Genetics
- Immunology
- Pediatrics
Background:
- Genetic predisposition is increasingly recognized in pediatric systemic lupus erythematosus (pSLE).
- Identifying specific genetic variants linked to immune dysregulation is crucial for understanding pSLE pathophysiology.
- Early-onset SLE in children may have a stronger genetic component than adult-onset disease.
Purpose of the Study:
- To identify genetic alterations in a patient with childhood-onset SLE.
- To analyze the immunological mechanisms associated with these genetic changes.
- To provide insights for improved diagnosis, prognosis, and treatment of pSLE.
Main Methods:
- Whole exome sequencing (WES) for genetic analysis.
- Sanger sequencing for mutation confirmation.
- Bioinformatic tools (Ingenuity Pathway Analysis, Enrichr, Cytoscape) for pathway and gene interaction analysis.
Main Results:
- A 2-year-old girl diagnosed with idiopathic thrombocytopenic purpura and SLE presented with characteristic clinical and serological findings.
- Three novel mutations were identified: double-stranded missense mutations in ACP5 (c.1152G>T and c.420G>A) and a single-stranded mutation in SAMHD1 (c.1423G>A).
- Bioinformatic analysis indicated these genes and their interactors are enriched in immune pathways implicated in SLE, particularly the type I interferon pathway.
Conclusions:
- Polymorphisms in ACP5 and SAMHD1 contribute to SLE susceptibility.
- Mutations in these genes may disrupt the type I interferon pathway, influencing SLE pathogenesis.
- Identification of these mutations aids in genetic counseling and suggests potential targeted therapies for pSLE.
Background:
The study of genetic predisposition to pediatric systemic lupus erythematosus (pSLE) has brought new insights into the pathophysiology of SLE, as it is hypothesized that genetic predisposition is greater in children. Furthermore, identifying genetic variants and linking disrupted genes to abnormal immune pathways and clinical manifestations can be beneficial for both diagnosis and treatment. Here, we identified genetic alterations in a patient with childhood-onset SLE and analyzed the immunological mechanisms behind them to support future diagnosis, prognosis, and treatment.
Methods:
Whole exome sequencing (WES) was adopted for genetic analysis of a patient with childhood-onset SLE. Gene mutations were confirmed by Sanger sequencing. Clinical data of this patient were collected and summarized. Ingenuity Pathway Analysis was used to provide interacting genes of the perturbed genes. Online Enrichr tool and Cytoscape software were used to analysis the related pathways of these genes.
Results:
We present a case of a 2-year-old girl who was diagnosed with idiopathic thrombocytopenic purpura (ITP) and SLE. The patient was characterized by cutaneous bleeding spots on both lower extremities, thrombocytopenia, decreased serum complements levels, increased urinary red blood cells, and positive ANA and dsDNA. The patient was treated with methylprednisolone and mycophenolate, but clinical remission could not be achieved. The genomic analysis identified three novel mutations in this pSLE patient, a double-stranded missense mutation in ACP5 (c.1152G>T and c.420G>A) and a single-stranded mutation in SAMHD1 (c.1423G>A). Bioinformatic analysis showed that these two genes and their interacting genes are enriched in the regulation of multiple immune pathways associated with SLE, including cytokine signaling and immune cell activation or function. Analysis of the synergistic regulation of these two genes suggests that abnormalities in the type I interferon pathway caused by genetic variants may contribute to the pathogenesis of SLE.
Conclusion:
The combined complexity of polymorphisms in the coding regions of ACP5 and SAMHD1 influences the susceptibility to SLE. Alterations in these genes may lead to abnormalities in the type I interferon pathway. Our study extends the spectrum of mutations in the ACP5 and SAMHD1 genes. The identification of these mutations could aid in the diagnosis of SLE with genetic counseling and suggest potential precise treatments for specific pathways.
