Kidney Injury by Variants in the COL4A5 Gene Aggravated by Polymorphisms in Slit Diaphragm Genes Causes Focal Segmental Glomerulosclerosis

Jenny Frese, Matthias Kettwig, Hildegard Zappel, Johannes Hofer, Hermann-Josef Gröne, Mato Nagel, Gere Sunder-Plassmann, Renate Kain, Jörg Neuweiler, Oliver Gross, Jenny Frese, Matthias Kettwig, Hildegard Zappel, Johannes Hofer, Hermann-Josef Gröne, Mato Nagel, Gere Sunder-Plassmann, Renate Kain, Jörg Neuweiler, Oliver Gross

Abstract

Kidney injury due to focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular disorder causing end-stage renal disease. Homozygous mutations in either glomerular basement membrane or slit diaphragm genes cause early renal failure. Heterozygous carriers develop renal symptoms late, if at all. In contrast to mutations in slit diaphragm genes, hetero- or hemizygous mutations in the X-chromosomal COL4A5 Alport gene have not yet been recognized as a major cause of kidney injury by FSGS. We identified cases of FSGS that were unexpectedly diagnosed: In addition to mutations in the X-chromosomal COL4A5 type IV collagen gene, nephrin and podocin polymorphisms aggravated kidney damage, leading to FSGS with ruptures of the basement membrane in a toddler and early renal failure in heterozygous girls. The results of our case series study suggest a synergistic role for genes encoding basement membrane and slit diaphragm proteins as a cause of kidney injury due to FSGS. Our results demonstrate that the molecular genetics of different players in the glomerular filtration barrier can be used to evaluate causes of kidney injury. Given the high frequency of X-chromosomal carriers of Alport genes, the analysis of genes involved in the organization of podocyte architecture, the glomerular basement membrane, and the slit diaphragm will further improve our understanding of the pathogenesis of FSGS and guide prognosis of and therapy for hereditary glomerular kidney diseases.

Keywords: alport syndrome; focal segmental glomerulosclerosis; glomerular basement membrane; kidney injury; modifier gene; nephrin; podocin; slit diaphragm.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(a) Pedigree of case 1. (b–f) Nephropathological evaluation of the kidney biopsy of patient II-1. (b,c) Light microscopy showing focal segmental glomerulosclerosis (FSGS) and slight mesangial matrix expansion. (d–f) Ultrastructural analysis showing gross broadening of the podocyte foot processes; partial loss of the slit diaphragm (black arrow); and splitting, thinning, and ruptures of the glomerular basement membrane (GBM) (arrowhead). (g) The course of disease during ACE-inhibitor therapy: proteinuria constantly decreased (arrow). The diagnostic timescale is indicated by the blue arrows. Magnification: (b,c) 400×, (d) 20,000×, (e) 8000×, (f) 25,000×.
Figure 2
Figure 2
(a) Pedigree of case 2. (b,c) Kidney biopsy of the mother (11 y) revealing partial GBM thinning, splitting, and laminations in the lamina densa, with plump podocyte (P) foot processes. (d–g) Kidney biopsy of the daughter (3 y). (d,e) Light microscopy showing relatively normal glomerular and tubulointerstitial structures. Electron microscopy uncovered GBM pathology with splitting and thinning, similar to the mother’s nephropathology. (h) The course of disease without therapy in this X-chromosomal COL4A5 genotype was unexpectedly very similar in the heterozygous girl (III-1) and her hemizygous brother (III-2): proteinuria constantly increased into the nephrotic range. Magnification: (b,c) 10,000×, (d,e) 400×, (f,g) 12,500×.
Figure 3
Figure 3
(a) Pedigree of case 3, with I-1 and family members (II-1, II-2, II-5, II-6, and II-8) living in Poland. Further evaluation was performed on family members living in Vienna (II-3, II-4, II-7, III-7, and III-12). Tx = kidney transplant. (b,c) Kidney biopsy in case II-3. Only a small core of renal tissue could be obtained for light microscopy. This tissue contained only one relatively intact glomerulus and three glomerular scars. The pathology was described as nonspecific and dominated by sclerosis. The glomerulus showed segmental scarring of the capillary loops (open arrowheads) and pronounced periglomerular fibrosis (solid arrowheads). The tubules (T) were dissociated by interstitial fibrosis, and thickening of the tubular basement membranes confirmed advanced atrophy. One small artery (Art) exhibited minimal intimal fibrosis. (d) Proteinuria and albuminuria in family members with and without additional slit diaphragm (SD) polymorphisms. Methenamine silver (b) and PAS staining (c); magnification: 400×.

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