Background/Objectives: X-linked Alport syndrome (XLAS) arises from pathogenic variants in COL4A5. Truncating variants are generally classified as severe, but whether clinically meaningful heterogeneity exists within this group remains unclear. This study aimed to establish a novel Col4a5 knock-in mouse model based on a clinical variant and to determine whether truncating mutation position influences disease severity. Methods: A de novo COL4A5 frameshift variant, c.2440delG, was identified in a patient with severe early-onset XLAS. A Col4a5-G814fs knock-in mouse was generated by CRISPR/Cas9 on the C57BL/6J inbred mouse strain background and compared with the established Col4a5-G5X nonsense model using survival analysis, serial functional measurements, kidney histopathology, transmission electron microscopy, and RNA sequencing. Results: The Col4a5-G814fs knock-in mouse was successfully generated and showed loss of glomerular α5(IV) collagen chain expression. Compared with G5X mice, G814fs mice exhibited shorter survival (median 141 vs. 161.5 days, p = 0.0004), earlier onset of proteinuria, and more severe kidney functional decline. By 16 weeks, G814fs mice also showed more severe glomerular basement membrane abnormalities and more extensive glomerulosclerosis. RNA sequencing revealed a shared inflammatory gene signature in both models, together with selective upregulation of genes related to the PPAR signaling pathway and fatty acid metabolism in G814fs kidneys. Conclusions: This study reports a novel de novo COL4A5 frameshift variant and establishes the first Col4a5-G814fs knock-in mouse model. Direct comparison with the G5X model shows that distinct truncating COL4A5 mutations can be associated with substantially different disease severity, providing a useful platform for future mechanistic and therapeutic studies in XLAS.

Background/Objectives: Fibronectin glomerulopathy (FNG) is a rare autosomal dominant inherited kidney disease. Approximately 40% of genetically confirmed FNG cases are associated with likely pathogenic variants in FN1. Patients with FNG have similar clinical features as those with chronic nephritis. Due to nonspecific clinical manifestations mimicking common childhood glomerular diseases, FNG poses significant diagnostic challenges in children, frequently resulting in delayed diagnosis. Case Description: A 9-year-old Chinese girl presented with manifestations suggestive of acute poststreptococcal glomerulonephritis (APSGN), including edema, hypertension, hypocomplementemia, nephrotic-range proteinuria (3.34 g/24 h), and microscopic hematuria (45–55 cells/HP). Despite resolution of edema and normalized complement C3 after initial therapy, proteinuria and hematuria persisted. Renal biopsy revealed prominent mesangial deposits extending to glomerular capillary walls, with strong fibronectin (FN) immunoreactivity and fibrillary electrondense deposits on electron microscopy. Genetic testing identified a heterozygous FN1 missense variant c.3051G>C (p.Trp1017Cys) in the proband and her asymptomatic father, classified as likely pathogenic per ACMG guidelines (supporting evidence: PS1, PM2, PP3, PP4). mRNA and cDNA sequencing confirmed the transcription of the mutant allele in the family members. Notably, these transcriptional analyses cannot provide direct evidence for the functional pathogenicity of the variant. The patient received combined angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) therapy, and renal function remained stable during 3 years of follow-up. Conclusions: The FN1 c.3051G>C represents a novel nucleotide variant, while the corresponding amino acid alteration p.Trp1017Cys has been reported in the previous literature. This case expands the variant spectrum of FN1 and emphasizes the critical value of renal biopsy and genetic testing for diagnosing FNG in pediatric patients with persistent renal manifestations after suspected APSGN. Family screening is essential for identifying asymptomatic carriers. Our findings also highlight the phenotypic heterogeneity of FNG.