PMC9237440_01
Histopathological findings from the native renal biopsy specimen. (A,B) Glomeruli showed moderate-to-severe mesangial hyperplasia and segmental interposition together with crescent formation in approximately 1/3 of the glomeruli. (C) Masson's trichrome staining showed a large amount of deposition in the mesangial and subendothelial areas. (D) Immunofluorescence revealed mild C3 positivity. (E) Real-time changes in creatinine and urine protein post transplantation [(A): 200x, (B-D): 400x].
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F1
As shown in Figure 1, the glomeruli showed moderate-to-severe mesangial expansion and segmental interposition, and Masson's trichrome staining showed a large amount of fuchsinophilic deposits in the mesangial and subendothelial areas. Twenty-seven months after transplantation, the patient's urine test showed protein 1+ and elevated serum creatinine 1.35 mg/dl (Figure 1E). Sanger sequencing site verification on the patient's first-generation relatives and confirmed that they all carried this variant at this ectopic site (Figure 3A and Supplementary material 1). Surprisingly, the patient's relatives carried the
Histopathological findings from the transplanted renal biopsy specimen. (A-C) Glomeruli were enlarged and lobular. There was a large amount of deposition in the mesangial and subendothelial areas together with a slight proliferation of mesangial cells. (D) C3 was positive with an exudative pattern in immunofluorescence. (E,F) Deposition showed an obscure granular or short fibrillar appearance with a much higher electron density. (G) DNAJB9 immunohistochemistry turned negative. (H) Fibronectin was the most abundant protein in both the native and transplanted kidneys. (I,J) Fibronectin immunohistochemistry staining in the native kidney (C) and the transplanted kidney (D) was strongly positive [(A): 200x, (B-D), (G), (I-J): 400x].
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F2
As Figure 2 shows, glomeruli were enlarged and lobular. Fibrillary glomerulopathy was suspected, but DNAJB9 immunohistochemistry was negative (Figure 2G). According to the mass spectrometry results (Figure 2H), we stained the fibronectin of the native and transplanted kidneys. The immunohistochemical results showed that fibronectin was diffused and strongly positive (Figures 2I,J). As illustrated in Figure 3D and Supplementary material 2, we can observe obvious changes in the structure.
(A) Mutation T C in the fibronectin gene in the family (red box): (1) patient's mother, (2) the patient, and (3) and (4) the patient's sisters. (B) Pedigrees of the family with the FN1 mutation. The arrow indicates the patient. An asterisk indicates a mutation site but no phenotype. (C) Schematic diagram of fibronectin. The fibronectin monomer consists of type I (gray), II (orange), and III (yellow) repeats and the alternatively spliced sites EDI, EDII, and IIICS. The three main heparin-binding domains and the binding sites for integrins are shown. (D) Normal (left) and mutant (right) fibronectin structures are shown. The p. Leu1974pro mutation introduced a neutral amino acid very close to the hydrophobic core of hep II.
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F3
Sanger sequencing site verification on the patient's first-generation relatives and confirmed that they all carried this variant at this ectopic site (Figure 3A and Supplementary material 1). Surprisingly, the patient's relatives carried the FN1 gene variant without symptoms (Figure 3B). FN1 interacted with cells and extracellular substances through the binding sites of integrin, heparin, and heparan sulfate proteoglycan. Each FN1 monomer consisted of homologous modules classified as type I, II, or III repeats (Figure 3C). As illustrated in Figure 3D and Supplementary material 2, we can observe obvious changes in the structure.