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Clinical Journal of the American... Jul 2021The glomerular basement membrane is a vital component of the filtration barrier of the kidney and is primarily composed of a highly structured matrix of type IV... (Review)
Review
The glomerular basement membrane is a vital component of the filtration barrier of the kidney and is primarily composed of a highly structured matrix of type IV collagen. Specific isoforms of type IV collagen, the 3(IV), 4(IV), and 5(IV) isoforms, assemble into trimers that are required for normal glomerular basement membrane function. Disruption or alteration in these isoforms leads to breakdown of the glomerular basement membrane structure and function and can lead to progressive CKD known as Alport syndrome. However, there is wide variability in phenotype among patients with mutations affecting type IV collagen that depends on a complex interplay of sex, genotype, and X-chromosome inactivation. This article reviews the genetic basis of collagen disorders of the kidney as well as potential treatments for these conditions, including direct alteration of the DNA, RNA therapies, and manipulation of collagen proteins.
Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Collagen Type IV; Gene Editing; Genetic Therapy; Humans; Molecular Chaperones; Nephritis, Hereditary; Protein Isoforms; RNA Interference; RNA, Small Interfering; mRNA Vaccines
PubMed: 33849932
DOI: 10.2215/CJN.19171220 -
Nephron 2023The term "thin basement membrane" (TBM) refers to a glomerular disorder characterized by diffuse uniform thinning of the glomerular basement membrane (GBM) on electron... (Review)
Review
The term "thin basement membrane" (TBM) refers to a glomerular disorder characterized by diffuse uniform thinning of the glomerular basement membrane (GBM) on electron microscopy. Patients with TBM usually show an isolated hematuria with excellent renal prognosis. However, some patients can develop proteinuria and progressive kidney dysfunction in the long term. Most patients with TBM are heterozygous for pathogenic variants in genes encoding for both the α3 and α4 chains of collagen IV, a major constituent of GBM. Such variants are responsible for a wide range of clinical and histological phenotypes. The differential diagnosis between TBM and autosomal-dominant Alport syndrome and IgA nephritis (IGAN) may be difficult in some cases. Patients who progress to chronic kidney disease may show clinicopathologic features similar to those of primary focal and segmental glomerular sclerosis (FSGS). Without a shared classification of these patients, the risk of misdiagnosis and/or underestimation of the risk of progressive kidney disease is real. New efforts are needed to understand the determinants of renal prognosis and recognize the early signs of renal deterioration, allowing a custom-made diagnosis and therapeutic approach. For this purpose, a practical and simple clinical approach is supplied.
Topics: Humans; Nephritis, Hereditary; Kidney; Glomerular Basement Membrane; Kidney Failure, Chronic; Collagen Type IV; Hematuria
PubMed: 36882005
DOI: 10.1159/000528243 -
International Journal of Molecular... Jun 2022Alport syndrome (AS) is the second most common cause of inherited chronic kidney disease. This disorder is caused by genetic variants on , and genes. These genes... (Review)
Review
Alport syndrome (AS) is the second most common cause of inherited chronic kidney disease. This disorder is caused by genetic variants on , and genes. These genes encode the proteins that constitute collagen type IV of the glomerular basement membrane (GBM). The heterodimer COL4A3A4A5 constitutes the majority of the GBM, and it is essential for the normal function of the glomerular filtration barrier (GFB). Alterations in any of collagen type IV constituents cause disruption of the GMB structure, allowing leakage of red blood cells and albumin into the urine, and compromise the architecture of the GFB, inducing inflammation and fibrosis, thus resulting in kidney damage and loss of renal function. The advances in DNA sequencing technologies, such as next-generation sequencing, allow an accurate diagnose of AS. Due to the important risk of the development of progressive kidney disease in AS patients, which can be delayed or possibly prevented by timely initiation of therapy, an early diagnosis of this condition is mandatory. Conventional biomarkers such as albuminuria and serum creatinine increase relatively late in AS. A panel of biomarkers that might detect early renal damage, monitor therapy, and reflect the prognosis would have special interest in clinical practice. The aim of this systematic review is to summarize the biomarkers of renal damage in AS as described in the literature. We found that urinary Podocin and Vascular Endothelial Growth Factor A are important markers of podocyte injury. Urinary Epidermal Growth Factor has been related to tubular damage, interstitial fibrosis and rapid progression of the disease. Inflammatory markers such as Transforming Growth Factor Beta 1, High Motility Group Box 1 and Urinary Monocyte Chemoattractant Protein- 1 are also increased in AS and indicate a higher risk of kidney disease progression. Studies suggest that miRNA-21 is elevated when renal damage occurs. Novel techniques, such as proteomics and microRNAs, are promising.
Topics: Biomarkers; Collagen Type IV; Fibrosis; Humans; Kidney; Nephritis, Hereditary; Vascular Endothelial Growth Factor A
PubMed: 35806283
DOI: 10.3390/ijms23137276 -
JCI Insight Jan 2022Alport syndrome (AS) is a genetic disorder caused by mutations in type IV collagen that lead to defective glomerular basement membrane, glomerular filtration barrier...
Alport syndrome (AS) is a genetic disorder caused by mutations in type IV collagen that lead to defective glomerular basement membrane, glomerular filtration barrier (GFB) damage, and progressive chronic kidney disease. While the genetic basis of AS is well known, the molecular and cellular mechanistic details of disease pathogenesis have been elusive, hindering the development of mechanism-based therapies. Here, we performed intravital multiphoton imaging of the local kidney tissue microenvironment in a X-linked AS mouse model to directly visualize the major drivers of AS pathology. Severely distended glomerular capillaries and aneurysms were found accompanied by numerous microthrombi, increased glomerular endothelial surface layer (glycocalyx) and immune cell homing, GFB albumin leakage, glomerulosclerosis, and interstitial fibrosis by 5 months of age, with an intermediate phenotype at 2 months. Renal histology in mouse or patient tissues largely failed to detect capillary aberrations. Treatment of AS mice with hyaluronidase or the ACE inhibitor enalapril reduced the excess glomerular endothelial glycocalyx and blocked immune cell homing and GFB albumin leakage. This study identified central roles of glomerular mechanical forces and endothelial and immune cell activation early in AS, which could be therapeutically targeted to reduce mechanical strain and local tissue inflammation and improve kidney function.
Topics: Animals; Capillaries; Cellular Microenvironment; Disease Models, Animal; Humans; Intravital Microscopy; Kidney Glomerulus; Male; Mice; Nephritis, Hereditary
PubMed: 34793332
DOI: 10.1172/jci.insight.152676 -
Kidney360 Mar 2022Alport syndrome is an inherited disorder characterized by progressive renal disease, variable sensorineural hearing loss, and ocular abnormalities. Although many...
BACKGROUND
Alport syndrome is an inherited disorder characterized by progressive renal disease, variable sensorineural hearing loss, and ocular abnormalities. Although many pathogenic variants in and have been identified in patients with autosomal Alport syndrome, synonymous mutations in these genes have rarely been identified.
METHODS
We conducted splicing analysis using Human Splicing Finder (HSF) and Alamut to predict splicing domain strength and disruption of the sites. Furthermore, we performed splicing assays using minigene constructs and mRNA analysis of patient samples to determine the pathogenicity of four synonymous variants detected in four patients with suspected autosomal dominant Alport syndrome ( [c.693G>A (p.Val231=)] and [c.1353C>T (p.Gly451=), c.735G>A (p.Pro245=), and c.870G>A (p.Lys290=)]).
RESULTS
Both and splicing assays showed exon skipping in two out of the four synonymous variants identified (c.735G>A and c.870G>A in ). Prediction analysis of wild-type and mutated sequences using HSF and Alamut suggested these two variants may lead to the loss of binding sites for several splicing factors, , in acceptor sites and exonic splicing enhancers. The other two variants did not induce aberrant splicing.
CONCLUSIONS
This study highlights the pitfalls of classifying the functional consequences of variants by a simple approach. Certain synonymous variants, although they do not alter the amino acid sequence of the encoded protein, can dramatically affect pre-mRNA splicing, as shown in two of our patients. Our findings indicate that transcript analysis should be carried out to evaluate synonymous variants detected in patients with autosomal dominant Alport syndrome.
Topics: Autoantigens; Collagen Type IV; Exons; Humans; Nephritis, Hereditary; Silent Mutation
PubMed: 35582193
DOI: 10.34067/KID.0005252021 -
Archives of Pathology & Laboratory... Feb 2009Alport syndrome and thin glomerular basement membrane nephropathy (TBMN) are genetically heterogeneous conditions characterized by structural abnormalities in the... (Review)
Review
CONTEXT
Alport syndrome and thin glomerular basement membrane nephropathy (TBMN) are genetically heterogeneous conditions characterized by structural abnormalities in the glomerular basement membrane and an initial presentation that usually involves hematuria. Approximately 40% of patients with TBMN are heterozygous carriers for autosomal recessive Alport syndrome, with mutations at the genetic locus encoding type IV collagen alpha(3) [alpha(3)(IV)] and alpha(4) chains. However, although the clinical course of TBMN is usually benign, Alport syndrome, particularly the X-linked form with mutations in the locus encoding the alpha(5) chain of type IV collagen [alpha(5)(IV)], typically results in end-stage renal disease. Electron microscopy is essential to diagnosis of TBMN and Alport syndrome on renal biopsy, although electron microscopy alone is of limited value in distinguishing between TBMN, the heterozygous carrier state of X-linked Alport syndrome, autosomal recessive Alport syndrome, and even early stages of X-linked Alport syndrome.
OBJECTIVES
To review diagnostic pathologic features of each of the above conditions, emphasizing the need for immunohistology for alpha(3)(IV) and alpha(5)(IV) in addition to electron microscopy to resolve this differential diagnosis on a renal biopsy. The diagnostic value of immunofluorescence studies for alpha(5)(IV) on a skin biopsy in family members of patients with Alport syndrome also is reviewed.
DATA SOURCES
Original and comprehensive review articles on the diagnosis of Alport syndrome and TBMN from the past 35 years, primarily the past 2 decades, and experience in our own renal pathology laboratory.
CONCLUSIONS
Although Alport syndrome variants and TBMN do not show characteristic light microscopic findings and can be difficult to differentiate from each other even by electron microscopy, using a combination of electron microscopy and immunohistology for alpha(3)(IV) and alpha(5)(IV) enables pathologists to definitively diagnose these disorders on renal biopsy in most cases.
Topics: Autoantigens; Collagen Type IV; Diagnosis, Differential; Glomerular Basement Membrane; Glomerulonephritis; Humans; Mutation; Nephritis, Hereditary
PubMed: 19195966
DOI: 10.5858/133.2.224 -
Kidney360 May 2023
Topics: Humans; Nephritis, Hereditary; Kidney; Fibrosis
PubMed: 37229728
DOI: 10.34067/KID.0000000000000136 -
Aging Jul 2019
Topics: Animals; Autoantigens; Collagen Type IV; Disease Models, Animal; Heart Failure; Humans; Mice; Nephritis, Hereditary; Phenotype; Stroke Volume
PubMed: 31305259
DOI: 10.18632/aging.102102 -
BMC Medical Genomics Aug 2023Alport syndrome (AS; OMIM#308,940) is a hereditary kidney disease that progresses over time and is distinguished by hearing loss and ocular irregularities. The syndrome...
BACKGROUND
Alport syndrome (AS; OMIM#308,940) is a hereditary kidney disease that progresses over time and is distinguished by hearing loss and ocular irregularities. The syndrome has three subtypes, namely X-linked (XL; OMIM#301,050), autosomal recessive (AR; OMIM#203,780), and autosomal dominant (AD; OMIM#104,200), which are categorized based on their respective modes of inheritance. XLAS is attributed to a pathogenic variant in the COL4A5 (OMIM*303,630) gene, which encodes the α5(IV) chain of type IV collagen (Col-IV). In contrast, ADAS and ARAS are the result of variants in the COL4A3 (OMIM*120,070) and COL4A4 (OMIM*120,131) genes, which encode the α3(IV) and α4(IV) chains of Col-IV, respectively. Typically, the diagnosis of AS necessitates hereditary or pathological assessments. The determination of splicing variants as pathogenic or non-pathogenic based on gene sequencing outcomes is challenging.
METHODS
In this study, we conducted exome sequencing and Sanger sequencing on two unrelated Chinese patients with AS. We identified a deletion variant c.4414delG in the COL4A5 gene and a splicing variant c.4298-20T > A in the same gene. In order to ascertain the impact of c.4298-20T > A on the synthesis of COL4A5 mRNA, we performed experiments involving minigene splicing. Additionally, we predicted the ability of these two variants to affect triple helix formation of α345(IV) using molecular dynamics methods.
RESULTS
The c.4414delG deletion variant caused a change in the genetic code of the COL4A5 gene. Specifically, it caused a shift in codon 1472 from encoding aspartate to encoding methionine. This shift resulted in a change of 75 amino acids in the protein sequence, ultimately leading to an early stop codon. This premature stop codon caused the production of a truncated α5(IV) chain with a predicted protein effect of p.D1472Mfs. The mRNA of the COL4A5 gene experienced intron 46 retention due to the splicing variant c.4298-20T > A, leading to the inclusion of six additional amino acids between amino acids 1432 and 1433 of the α5(IV) chain. This variant is predicted to have a protein effect of p.(P1432_G1433insDYFVEI). The impact of two variants, c.4414delG and c.4298-20T > A, on the aggregation region for α3(IV), α4(IV), and α5(IV) trimerisation were studied using molecular dynamics simulations. Results showed that the deletion variant c.4414delG had a significantly stronger disruption on NC1, compared to the splicing variant c.4298-20T > A. This difference in impact is consistent with the varying clinical phenotypes observed in the two patients. Based on the American College of Medical Genetics and Genomics (ACMG) classification criteria and guidelines for genetic variants, the deletion variant c.4414delG was rated as pathogenic while the splicing variant c.4298-20T > A was rated as likely-pathogenic.
CONCLUSION
Our study has identified two novel pathogenic loci, the deletion variant c.4414delG and the splicing variant c.4298-20T > A, associated with XLAS. This finding expands the genetic spectrum of XLAS. We suggest that molecular dynamics can effectively model the effect of genetic variation on α345(IV) trimerization, which may offer valuable insights into the mechanisms of XLAS pathogenesis.
Topics: Humans; Amino Acids; Collagen Type IV; Deafness; Introns; Molecular Dynamics Simulation; Nephritis, Hereditary
PubMed: 37596645
DOI: 10.1186/s12920-023-01623-7 -
BMC Nephrology Jul 2019Alport syndrome is a rare genetic kidney disease, and rheumatoid arthritis as a common autoimmune disease also causes renal lesions in addition to arthritis. The overlap... (Review)
Review
BACKGROUND
Alport syndrome is a rare genetic kidney disease, and rheumatoid arthritis as a common autoimmune disease also causes renal lesions in addition to arthritis. The overlap of them has rarely been reported.
CASE PRESENTATION
A 44-year-old man had a history of multi-joint swelling and pain for more than half a year. His laboratory data with double positive for rheumatoid factor and anticitrullinated protein antibodies further supported the diagnosis of early rheumatoid arthritis. His previous medical history including progressive hearing loss for several years and microhematuria for one year attracted our attention. Renal biopsy showed thin basement membrane nephropathy and lymphocytes infiltration of interstitium. To make a precise diagnosis, targeted Next Generation Sequencing (NGS) of an inherited renal disease panel including Alport syndrome genes was performed, which revealed the missense mutation in COL4A5 (c.1351 T > C, p.Cys451Arg). Further in silico analyses predicted that the p. Cys451Arg mutation is functionally "damaging", so the diagnosis of Alport syndrome was finally proved. The patient has been receiving the treatment of total glucosides of paeony and leflunomide for rheumatoid arthritis, and Cozaar 50 mg for the protection of kidney so far. During the 10-months follow-up, swelling and tenderness of the joints in this patient had been generally relieved, with no obvious improvement in microhematuria and a slight increase in proteinuria.
CONCLUSION
we reported an adult man with the coexistence of rheumatoid arthritis and Alport syndrome with the missense mutation in COL4A5 (c.1351 T > C, p.Cys451Arg). Whether the overlap of them is occasional or has a common pathophysiological mechanism is still unclear.
Topics: Adult; Arthritis, Rheumatoid; Humans; Male; Nephritis, Hereditary
PubMed: 31337345
DOI: 10.1186/s12882-019-1462-3