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.
Highlights
Focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular disorder causing end-stage renal disease (ESRD) in the United States [1]
Podocyte injury plays a critical role in the pathogenesis of proteinuric kidney diseases, as podocytes are important for maintaining the glomerular filtration barrier [2]
Patient 1 was the index patient, in whom a severe kidney phenotype and glomerular basement membrane (GBM) ruptures led to the discovery that in FSGS due to genetic GBM diseases, such as Alport syndrome (AS), polymorphisms in slit diaphragm genes can aggravate kidney damage
Summary
Focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular disorder causing end-stage renal disease (ESRD) in the United States [1]. Podocyte injury plays a critical role in the pathogenesis of proteinuric kidney diseases, as podocytes are important for maintaining the glomerular filtration barrier [2] They restore crucial components of the glomerular basement membrane (GBM), such as α3/α4/α5 type IV collagen chains (COL4A3/4/5), and of the slit diaphragm, such as nephrin (NPHS1) and podocin (NPHS2). Homozygous or hemizygous mutations in glomerular filtration barrier genes, such as the COL4A3/4/5 genes, result in Alport syndrome (AS) [3,4,5], while homozygous mutations in the NPHS1 and NPHS2 genes result in congenital nephrotic syndrome [6,7] The development of these syndromes leads to early ESRD. In addition to mutations in the XLAS-related COL4A5 gene, nephrin and podocin polymorphisms seem to have aggravated kidney damage, including severe FSGS with GBM ruptures in a toddler and unusually early renal failure in heterozygous girls
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
