{Reference Type}: Case Reports
{Title}: Novel variants in CRB2 targeting the malfunction of slit diaphragm related to focal segmental glomerulosclerosis.
{Author}: Yang Q;Tang D;Gan C;Bai M;Song X;Jiang W;Li Q;Chen Y;Zhang A;Wang M;
{Journal}: Pediatr Nephrol
{Volume}: 39
{Issue}: 1
{Year}: 2024 Jan 15
{Factor}: 3.651
{DOI}: 10.1007/s00467-023-06087-6
{Abstract}: <B>BACKGROUND: </B>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.<BR><B>METHODS: </B>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.<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>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. A higher resolution version of the Graphical abstract is available as Supplementary information.