Alport Syndrome with a Peculiar Pattern of Distribution of the α3–α6 Chains of Type IV Collagen in Renal Basement Membrane

Nephron ◽  
1998 ◽  
Vol 80 (1) ◽  
pp. 115-117 ◽  
Author(s):  
Mikiya Fujieda ◽  
Fumiko Endo ◽  
Yutaka Morisawa ◽  
Ichiro Naito ◽  
Yoshikazu Sado ◽  
...  
Keyword(s):  
Basement Membrane ◽  
Alport Syndrome ◽  
Type Iv Collagen ◽  
Type Iv

scholarly journals Autosomal recessive Alport syndrome: mutation in the COL4A3 gene in a woman with Alport syndrome and posttransplant antiglomerular basement membrane nephritis.

1995 ◽  
Vol 5 (9) ◽  
pp. 1714-1717
Author(s):  
J Ding ◽  
J Stitzel ◽  
P Berry ◽  
E Hawkins ◽  
C E Kashtan
Keyword(s):  
Basement Membrane ◽  
Renal Disease ◽  
Alport Syndrome ◽  
Autosomal Recessive ◽  
Type Iv Collagen ◽  
Premature Stop Codon ◽  
Sensorineural Deafness ◽  
Type Iv ◽  
Base Pair Deletion ◽  
Carboxy Terminal

Autosomal recessive Alport syndrome can arise from a mutation in either of the genes COL4A3 and COL4A4 on chromosome 2, which encode, respectively, the alpha 3 and alpha 4 chains of Type IV collagen. This report describes a mutation in COL4A3 in a girl who presented at age 5 with hematuria and proteinuria, lacking any family history of renal disease. Renal biopsy at age 8 showed immunoglobulin A nephropathy and Alport syndrome. Sensorineural deafness developed during adolescence, and the patient's renal disease progressed to terminal renal failure by age 20. She received a living related donor renal allograft at age 20 and developed antiglomerular basement membrane nephritis of the allograft 8 months after transplantation. Amplification and sequencing of exon 5 of COL4A3 (counting from the 3' end of the gene) revealed a 7-base-pair deletion, producing a shift of the reading frame and the creation of a premature stop codon. Each parent was heterozygous for the normal and mutant exon 5 sequences. This mutation in COL4A3 would result in the loss of 222 amino acids from the carboxy-terminal noncollagenous domain of the alpha 3(IV) chain. The mutant chain would be unable to form trimers with other Type IV collagen alpha chains. In addition, the mutant chain would lack the Goodpasture epitope, which resides in the carboxy-terminal noncollagenous domain of the alpha 3(IV) chain. The absence of this epitope may underly the subsequent development of anti-glomerular basement membrane nephritis in the allograft.

Alport Syndrome and Thin Glomerular Basement Membrane Nephropathy: A Practical Approach to Diagnosis

2009 ◽  
Vol 133 (2) ◽  
pp. 224-232 ◽  
Author(s):  
Mark Haas
Keyword(s):  
Electron Microscopy ◽  
Basement Membrane ◽  
Renal Biopsy ◽  
Glomerular Basement Membrane ◽  
Alport Syndrome ◽  
Autosomal Recessive ◽  
Type Iv Collagen ◽  
The Past ◽  
Type Iv ◽  
Pathologic Features

Abstract Context.—Alport syndrome and thin glomerular basement membrane nephropathy (TBMN) are genetically heterogenous 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 α3 [α3(IV)] and α4 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 α5 chain of type IV collagen [α5(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 α3(IV) and α5(IV) in addition to electron microscopy to resolve this differential diagnosis on a renal biopsy. The diagnostic value of immunofluorescence studies for α5(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 α3(IV) and α5(IV) enables pathologists to definitively diagnose these disorders on renal biopsy in most cases.

scholarly journals Spectrum of collagen type IV nephropathies: From thin basement membrane nephropathy to Alport syndrome

2008 ◽  
Vol 136 (Suppl. 4) ◽  
pp. 323-326 ◽  
Author(s):  
Alenka Vizjak ◽  
Dusan Ferluga
Keyword(s):  
Basement Membrane ◽  
Glomerular Basement Membrane ◽  
Alport Syndrome ◽  
Type Iv Collagen ◽  
Mutation Screening ◽  
Glomerular Sclerosis ◽  
Collagen Type Iv ◽  
Dominant Type ◽  
Thin Basement Membrane Nephropathy ◽  
Type Iv

Alport syndrome and thin basement membrane nephropathy are common causes of persistent familial haematuria. They are associated with various mutations in type IV collagen genes. Mutations in genes, coding for ?5 chain of collagen IV, cause X-linked Alport syndrome, whereas mutations in genes for ?3 and ?4 chains can cause the autosomal recessive and autosomal dominant type of Alport syndrome or benign familial haematuria with thin basement membrane nephropathy. In view of the wide spectrum of phenotypes, an exact diagnosis is sometimes difficult to achieve. Few studies of genotype-phenotype correlations in Alport syndrome have shown that various types of mutations may be a significant predictor of the severity of disease. Histopathologic findings in Alport syndrome vary from normal kidney to nonspecific focal segmental and global glomerular sclerosis with characteristic ultrastructural finding of thickening and splitting of the glomerular basement membrane. Thin basement membrane nephropathy is characterized by diffuse thinning of the glomerular basement membrane on an ultrastructural level, while by light microscopy glomeruli are mostly unremarkable. Because of present limitations of mutation screening techniques, kidney biopsy with mandatory ultrastructural analysis and immunohistochemistry examination for type IV collagen ? chains remains a standard approach for establishing diagnosis and determining the mode of transmission of the disease.

scholarly journals The Genetics, Current Research, and Future Treatment of Alport Syndrome

2017 ◽  
Vol 6 (1) ◽  
pp. 1-7
Author(s):  
Elise Alexandra Kikis ◽  
Emily Holland Williams
Keyword(s):  
Basement Membrane ◽  
End Stage Renal Disease ◽  
Alport Syndrome ◽  
Autosomal Recessive ◽  
Type Iv Collagen ◽  
Autosomal Dominant ◽  
Basement Membranes ◽  
Type Iv ◽  
Stage Renal Disease ◽  
End Stage

Alport syndrome is a type IV collagen disease that affects the glomerular basement membrane of approximately one in every 5000 people. The disease was first described by A. Cecil Alport in 1927 as “a dominantly inherited hereditary nephritis.” The three genotypes of the disease are X-linked dominant, autosomal recessive, and autosomal dominant. The X-linked dominant genotype is the most common, accounting for 80% of all cases of Alport syndrome, affecting mainly men. The autosomal recessive and autosomal dominant types affect men and women equally. Alport syndrome is caused by mutations on the COL4A3, COL4A4, and COL4A5 genes, which code the ?3, ?4, and ?5 (IV) chains that make up type IV collagen molecules, an important component of basement membranes. Thus, Alport syndrome results in malformed basement membranes, with symptoms including renal impairment, hematuria, bilateral sensorineural hearing loss, and an abnormal structure of the glomerular basement membrane. Alport syndrome also often progresses to end-stage renal disease, especially in men with X-linked Alport syndrome. At this point, there is no cure for Alport syndrome. However, there are many successful treatments for its symptoms. Angiotensin-converting enzyme (ACE) inhibitors are often given to patients in the early stages of Alport syndrome. For patients with end-stage renal disease, dialysis or kidney transplants are considered the best course of action.

scholarly journals Mutation in alpha 5(IV) collagen chain gene in nonfamilial hematuria.

1995 ◽  
Vol 6 (2) ◽  
pp. 264-268
Author(s):  
K Kitagawa ◽  
K Nakanishi ◽  
K Iijima ◽  
H Nishio ◽  
Y Sado ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Basement Membrane ◽  
Glomerular Basement Membrane ◽  
Alport Syndrome ◽  
Type Iv Collagen ◽  
Chain Reaction ◽  
Col4a5 Gene ◽  
Abnormal Expression ◽  
Type Iv ◽  
Polymerase Chain

Alport syndrome is an inherited disorder characterized by progressive nephritis with ultrastructural basket-weave changes of the glomerular basement membrane and neurosensory deafness. Mutations in the COL4A5 gene encoding the Type IV collagen alpha 5 chain have been reported to occur in patients with X-linked Alport syndrome. A girl with hematuric nephritis, characteristic basket-weave glomerular basement membrane changes, and abnormal expression of the Type IV collagen alpha 5 chain immunohistochemically, but no family history of nephritis, was identified. Mutation detection enhancement gel electrophoresis of the polymerase chain reaction-amplified exons of COL4A5 from this patient revealed a sequence variant in the exon 50 region. Sequence analysis of her polymerase chain reaction product demonstrated a single-base (C; nucleotide 4728 from the 5' end) deletion in exon 50. This novel mutation alters the reading frame and introduces a translation stop codon that would be expected to result in a noncollagenous domain with only 209, instead of the normal 229, amino acid residues. Gene tracking with restriction enzyme AfIIII demonstrated that her mother was normal. These findings represent a new mutation of the X-linked Alport syndrome in this patient and demonstrate that a COL4A5 gene mutation causes the abnormal expression of Type IV collagen alpha 5 chain protein.

scholarly journals Dynamically remodeled hepatic extracellular matrix predicts prognosis of early-stage cirrhosis

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Yuexin Wu ◽  
Yuyan Cao ◽  
Keren Xu ◽  
Yue Zhu ◽  
Yuemei Qiao ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Basement Membrane ◽  
Type Iv Collagen ◽  
Patient Survival ◽  
Early Stage ◽  
Ecm Remodeling ◽  
Type Iv ◽  
Ecm Proteins ◽  
Stage Disease ◽  
Cirrhotic Patients

AbstractLiver cirrhosis remains major health problem. Despite the progress in diagnosis of asymptomatic early-stage cirrhosis, prognostic biomarkers are needed to identify cirrhotic patients at high risk developing advanced stage disease. Liver cirrhosis is the result of deregulated wound healing and is featured by aberrant extracellular matrix (ECM) remodeling. However, it is not comprehensively understood how ECM is dynamically remodeled in the progressive development of liver cirrhosis. It is yet unknown whether ECM signature is of predictive value in determining prognosis of early-stage liver cirrhosis. In this study, we systematically analyzed proteomics of decellularized hepatic matrix and identified four unique clusters of ECM proteins at tissue damage/inflammation, transitional ECM remodeling or fibrogenesis stage in carbon tetrachloride-induced liver fibrosis. In particular, basement membrane (BM) was heavily deposited at the fibrogenesis stage. BM component minor type IV collagen α5 chain expression was increased in activated hepatic stellate cells. Knockout of minor type IV collagen α5 chain ameliorated liver fibrosis by hampering hepatic stellate cell activation and promoting hepatocyte proliferation. ECM signatures were differentially enriched in the biopsies of good and poor prognosis early-stage liver cirrhosis patients. Clusters of ECM proteins responsible for homeostatic remodeling and tissue fibrogenesis, as well as basement membrane signature were significantly associated with disease progression and patient survival. In particular, a 14-gene signature consisting of basement membrane proteins is potent in predicting disease progression and patient survival. Thus, the ECM signatures are potential prognostic biomarkers to identify cirrhotic patients at high risk developing advanced stage disease.

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