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Novel variants in CRB2 targeting the malfunction of slit diaphragm related to focal segmental glomerulosclerosis

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Abstract

Background

Focal segmental glomerulosclerosis (FSGS) is a leading cause of steroid-resistant nephrotic syndrome (SRNS) that predominantly affects the podocytes. While mutations in genes causing pediatric SRNS have enhanced our understanding of FSGS, the disease’s etiology remains complex and poorly understood.

Methods

Whole exome sequencing (WES) was performed on a 9-year-old girl with SRNS associated with FSGS (SRNS–FSGS). We analyzed the expression of CRB2, slit diaphragm (SD)-associated proteins, and sphingosine 1-phosphate receptor 1 (S1PR1) in the proband and CRB2 knock-down podocytes.

Results

In this study, we identified two novel compound heterozygous mutations in the Crumbs homolog 2 (CRB2) gene (c.2905delinsGCCACCTCGCGCTGGCTG, p.T969Afs*179 and c.3268C > G, p.R1090G) in a family with early-onset SRNS–FSGS. Our findings demonstrate that these CRB2 abnormalities were the underlying cause of SRNS–FSGS. CRB2 defects led to the dysfunction of podocyte SD-related proteins, including podocin, nephrin, and zonula occludens-1 (ZO-1), by reducing the phosphorylation level of S1PR1. Interestingly, the podocytic cytoskeleton remained unaffected, as demonstrated by normal expression and localization of synaptopodin. Our study also revealed a secondary decrease in CRB2 expression in idiopathic FSGS patients, indicating that CRB2 mutations may cause FSGS through a previously unknown mechanism involving SD-related proteins.

Conclusions

Overall, our findings shed new light on the pathogenesis of SRNS–FSGS and revealed that the novel pathogenic mutations in CRB2 contribute to the development of FSGS through a previously unknown mechanism involving SD-related proteins.

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Data availability

All data and materials included in this study are available upon request by contacting with the corresponding author.

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Acknowledgements

We thank Dr. Yupeng Cun. from the Children’s Hospital of Chongqing Medical University for helpful discussions; the Children’s Hospital of Nanjing Medical University for expert assistance with the cell laboratory.

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Authors and Affiliations

  1. Pediatric Research Institute, Department of Nephrology Children’s Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing Key Laboratory of Child Infection and Immunity, Children’s Hospital of Chongqing Medical University, Chongqing, People’s Republic of China

    Qing Yang, Chun Gan, Xiaomei Song, Wei Jiang, Qiu Li & Mo Wang

  2. Department of Pediatrics, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, 621000, Sichuan, China

    Dan Tang

  3. Department of Nephrology, State Key Laboratory of Reproductive Medicine, Children’s Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, China

    Mi Bai & Aihua Zhang

  4. Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, People’s Republic of China

    Yaxi Chen

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Contributions

Performing the experiments, formal analysis, and writing the manuscript: Qing Yang. Amending the manuscript and designing the experiments: Mo Wang. Collecting clinical data: Tang Dan, Xiaomei Song, and Chun Gan. Formal analysis and amending of the manuscript: Wei Jiang. Technically guiding the experiments: Aihua Zhang, Yaxi Chen, and Mi Bai.

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Correspondence to Mo Wang.

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Yang, Q., Tang, D., Gan, C. et al. Novel variants in CRB2 targeting the malfunction of slit diaphragm related to focal segmental glomerulosclerosis. Pediatr Nephrol 39, 149–165 (2024). https://doi.org/10.1007/s00467-023-06087-6

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