PMC8326751_01
Renal biopsy findings. (A-C) Biopsy from the proband. (A) Mild mesangial cells and matrix proliferation is seen (PASM). (B) Lamina densa lamellation and splitting is seen along the GBM on electron microscopy. (C) Complete absence of alpha5 staining in the glomerular and tubular basement membranes. (D-F) Biopsy from the elder sister. (D) Segmental mesangial cells and matrix proliferation is seen (PASM). (E) Electron microscopy revealed splitting GBM. (F) The alpha5 staining in the glomerular and tubular basement membranes was absent.
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F1
Light microscopy showed glomerular mesangial mild hyperplasia, mild tubulointerstitial lesions (Figure 1A). Electron microscopy demonstrated mesangial electron-dense deposits, podocyte foot process effacement, and segmental GBM with splitting appearance (Figure 1B). However, alpha5 was completely absent in both glomeruli and tubules (Figure 1C). Light microscopy of kidney biopsy showed segmental mesangial proliferative glomerulonephritis (Figure 1D). Electron microscopy finding revealed splitting of GBM (Figure 1E). Immunofluorescence was all negative including alpha5 chain (Figure 1F).
DNA analysis of the patient and family members and structural evaluation of mutant FB p.Ser687Pro. (A) Direct sequencing of patient genomic DNA shows the c.2054_2057del (p.Ser687Profs*16) novel genetic variant in exon 16 of the CFB gene, c.2999G > T (p.Gly1000Val) in exon 34 of the COL4A5 gene. (B) The pedigrees of the family with digenic inheritance. (C) Visualization of the mutant FB. The figure was prepared using swiss-model. Pr, proteinuria; He, hematuria. Red arrow means the position of mutation. Red square means the impact of the frameshift mutation on splice site changes and protein features.
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F2
The result demonstrated CFB c.2054_2057del (p.Ser687Profs*16) variant and X-linked COL4A5 c.2999G > T (p.Gly1000Val) variant (Figure 2A). And his elder sister has the same genetic variants as the proband (Figure 2B). The frameshift mutation has been predicted by rare exome variant ensemble learner as "likely pathogenic," which has an impact on splice site changes and protein features might be affected (Figure 2C).
Immunohistochemical staining of complement components. (A-D) For the proband. (E-H) For his elder sister. (A,E) FB staining within glomerular capillary and segmental mesangial for the proband and his elder sister, respectively. (B,F) C3c staining mainly along glomerular capillary for the proband and his elder sister, respectively. (C,G) Weak glomerular staining with C3d along glomerular capillary for the proband and his elder sister, respectively. (D,H) Absent glomerular C4d staining for the proband and his elder sister, respectively.
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F3
FB, C3c, and C3d were all positive in the proband and his elder sister, C4d, was negative in glomeruli (Figure 3). Furthermore, the plasma FB levels in the proband and his sister were 0.168 g/L and 0.3 g/L (normal range: 0.19-0.5 g/L), respectively.