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Background <p>Previous genome-wide association studies (GWAS) have associated chronic kidney disease with <i>AFG2B</i> variants. The AFG2B protein is linked to key immune-regulating processes through its interaction with proteasome proteins implicated in systemic inflammation. Dysregulation of these processes is a key factor in the onset of childhood-onset systemic lupus erythematosus (cSLE). This study aimed to investigate the frequency of <i>AFG2B</i> gene variants and the renal expression of the AFG2B protein in cSLE.</p> Methods <p>This two-phase, cross-sectional observational study included 45 patients with cSLE from a tertiary hospital in Brazil. In the first phase, we determined the frequency of variants in the <i>AFG2B</i> gene using PCR followed by Sanger sequencing. In the second phase, we analyzed AFG2B protein expression via immunohistochemistry in renal biopsies from patients with lupus nephritis (LN) and analyzed two publicly available databases from the Gene Expression Omnibus (GEO)—GSE32591 and GSE127797. To compare AFG2B expression in the LN, we used renal biopsy samples from patients undergoing nephrectomy for non-renal diseases (disease-free controls). We also performed modeling and molecular dynamics of AFG2B protein variants with pathogenic potential.</p> Results <p>One patient with cSLE (2.2%) had a missense variant in exon 5 of the <i>AFG2B</i> gene (c.1774&#xa0;A &gt; G); molecular dynamics studies indicated this variant (p.N592D) is more stable than the wild-type protein. Twenty-five patients (55.5%) had an intronic variant (g.12211&#xa0;A &gt; G), and one patient (2.2%) had a novel intronic variant in heterozygosity (g.13196&#xa0;A &gt; G). Kidney tissue samples from patients with cSLE exhibited significantly increased AFG2B protein expression compared to normal kidney tissues (<i>p</i> &lt; 0.01). We also observed a positive correlation between AFG2B protein expression in the tubules and the urinary protein-to-creatinine ratio (UPCR) in patients with cSLE.</p> Conclusions <p>AFG2B protein expression is significantly elevated in the renal tissues of patients with LN compared to that in controls. Furthermore, its expression in renal tubules correlated positively with the UPCR. These results suggest a potential role for this gene in the pathophysiology of cSLE and warrant further functional investigation.</p>

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AFG2B gene variants and elevated protein expression in lupus nephritis: new insights into childhood-onset systemic lupus erythematosus

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月13日

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  • Paola Pinheiro Kahwage,
  • Graziella Ribeiro de Sousa,
  • Ronald Rodrigues de Moura,
  • Fabiano Pinto Saggioro,
  • Inalda Facincani,
  • Denise do Nascimento Queiroga,
  • Veridiana Kiill Suazo,
  • Rosane Gomes de Paula Queiroz,
  • Davi Casale Aragon,
  • Virginia Paes Leme Ferriani,
  • Paula Sandrin-Garcia,
  • Luciana Martins de Carvalho

摘要

Background

Previous genome-wide association studies (GWAS) have associated chronic kidney disease with AFG2B variants. The AFG2B protein is linked to key immune-regulating processes through its interaction with proteasome proteins implicated in systemic inflammation. Dysregulation of these processes is a key factor in the onset of childhood-onset systemic lupus erythematosus (cSLE). This study aimed to investigate the frequency of AFG2B gene variants and the renal expression of the AFG2B protein in cSLE.

Methods

This two-phase, cross-sectional observational study included 45 patients with cSLE from a tertiary hospital in Brazil. In the first phase, we determined the frequency of variants in the AFG2B gene using PCR followed by Sanger sequencing. In the second phase, we analyzed AFG2B protein expression via immunohistochemistry in renal biopsies from patients with lupus nephritis (LN) and analyzed two publicly available databases from the Gene Expression Omnibus (GEO)—GSE32591 and GSE127797. To compare AFG2B expression in the LN, we used renal biopsy samples from patients undergoing nephrectomy for non-renal diseases (disease-free controls). We also performed modeling and molecular dynamics of AFG2B protein variants with pathogenic potential.

Results

One patient with cSLE (2.2%) had a missense variant in exon 5 of the AFG2B gene (c.1774 A > G); molecular dynamics studies indicated this variant (p.N592D) is more stable than the wild-type protein. Twenty-five patients (55.5%) had an intronic variant (g.12211 A > G), and one patient (2.2%) had a novel intronic variant in heterozygosity (g.13196 A > G). Kidney tissue samples from patients with cSLE exhibited significantly increased AFG2B protein expression compared to normal kidney tissues (p < 0.01). We also observed a positive correlation between AFG2B protein expression in the tubules and the urinary protein-to-creatinine ratio (UPCR) in patients with cSLE.

Conclusions

AFG2B protein expression is significantly elevated in the renal tissues of patients with LN compared to that in controls. Furthermore, its expression in renal tubules correlated positively with the UPCR. These results suggest a potential role for this gene in the pathophysiology of cSLE and warrant further functional investigation.