Autosomal recessive Alport syndrome: Immunohistochemical study of type IV collagen chain distribution

Abstract. Mutations in either the COL4A3 or the COL4A4 genes, encoding the α3 and α4 chains of type IV collagen, are responsible for the autosomal-recessive form of Alport syndrome, a progressive hematuric nephropathy characterized by glomerular basement membrane abnormalities. Reported here are the complete COL4A3 exon-intron structure and a comprehensive screen for mutations of the 52 COL4A3 exons in 41 unrelated patients diagnosed as having autosomal Alport syndrome. This resulted in the identification of 21 mutations that are expected to be causative. Furthermore, it is shown that heterozygous COL4A3 missense mutations, when symptomatic, can be associated with a broad range of phenotypes, from familial benign hematuria to the complete features of Alport syndrome nephropathy.

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

Journal of the American Society of Nephrology ◽

10.1681/asn.v591714 ◽

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.

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

Archives of Pathology & Laboratory Medicine ◽

10.5858/133.2.224 ◽

2009 ◽

Vol 133 (2) ◽

pp. 224-232 ◽

Cited By ~ 2

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.

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Spectrum of clinical features and type IV collagen -chain distribution in Chinese patients with Alport syndrome

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfl394 ◽

2006 ◽

Vol 21 (11) ◽

pp. 3146-3154 ◽

Cited By ~ 15

Author(s):

G. Wei ◽

L. Zhihong ◽

C. Huiping ◽

Z. Caihong ◽

C. Zhaohong ◽

...

Keyword(s):

Clinical Features ◽

Alport Syndrome ◽

Type Iv Collagen ◽

Chinese Patients ◽

Type Iv ◽

Collagen Chain

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

Journal of Student Research ◽

10.47611/jsr.v6i1.269 ◽

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.

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Complete primary structure of the triple-helical region and the carboxyl-terminal domain of a new type IV collagen chain, alpha 5(IV).

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)77414-0 ◽

1990 ◽

Vol 265 (23) ◽

pp. 13758-13766

Author(s):

T. Pihlajaniemi ◽

E.R. Pohjolainen ◽

J.C. Myers

Keyword(s):

Primary Structure ◽

Type Iv Collagen ◽

Terminal Domain ◽

Type Iv ◽

Carboxyl Terminal Domain ◽

New Type ◽

Carboxyl Terminal ◽

Collagen Chain ◽

Helical Region ◽

Complete Primary Structure

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Diagnostic Value of Type IV Collagen Expression in Renal Glomeruli at Alport’s Syndrome

Rossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics) ◽

10.21508/1027-4065-2020-65-6-42-49 ◽

2021 ◽

Vol 65 (6) ◽

pp. 42-49

Author(s):

M. E. Aksenova ◽

P. E. Povilaitite ◽

N. E. Konkova ◽

V. V. Dlin

Keyword(s):

Electron Microscopy ◽

Type Iv Collagen ◽

Immunohistochemical Study ◽

Immunohistochemical Method ◽

Alport's Syndrome ◽

Alport’S Syndrome ◽

Type Iv ◽

Renal Glomeruli ◽

Syndrome Diagnosis

The Alport’s syndrome is the hereditary multisystem disease characterized by the development of the progressive nephropathy. The early diagnosis and subsequent prescription of nephroprotective therapy improves significantly the nephrological prognosis. Purpose of the Study. Determine the value of the immunohistochemical method for the Alport’s syndrome diagnosis. Material and methods. The clinical, laboratory and morphological data of 35 patients with suspected Alport’s syndrome (13 years of age [11; 16]; 18 boys and 17 girls) examined in the Nephrology Department in 2013–2019 were summarized. The study of the renal tissue included the light, immunofluorescence, electron microscopy of the kidney biopsy sample, determination of the expression of α1, α3 and α5 chains of type IV collagen in the renal glomeruli using the immunohistochemical method; the genetic testing was carried out for 26 patients. The children were divided into groups depending on the glomerular expression of α5 chain of type IV collagen: normal (group 1, n=18), decreased (group 2, n=4), negative (group 3, n=13). Results are as the following: The disorder of the expression of α5 chain was detected in ¾ (q = 0.78) patients with genetically confirmed Alport’s syndrome and in almost all children with the X-linked variant of the disease (q = 0.94). Results. Based on the genetic testing, the Alport’s syndrome was confirmed in ¼ of the children of the 1st group (the children with the heterozygous variants of COL4A3, COL4A5 genes) and in all children of the 2nd and 3rd groups (COL4A5 variants). The sensitivity/ specificity of the immunohistochemical study for the Alport’s syndrome diagnosis was 78% /100%, that of the electron microscopy – 93% /87%. The predictive value of the positive/negative result of the immunohistochemical study was 100% /66%, that of the electron microscopy – 95% / 88% compared with 100% / 88% with the combine use of two methods. Conclusion. The determination of the expression of α5 chain of type IV collagen in the renal glomeruli has the independent diagnostic value, but it is inferior to the electron microscopy in the heterozygous variants of the Alport’s syndrome. The high specificity of the immunohistochemical method makes it possible to confirm the Alport’s syndrome in the case of the change in the expression of α5 chain of type IV collagen in the renal glomeruli.

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The Basement Membranes in Sarcomatoid Carcinomas. An Immunohistochemical Study

Tumori Journal ◽

10.1177/030089169307900210 ◽

1993 ◽

Vol 79 (2) ◽

pp. 128-132 ◽

Cited By ~ 6

Author(s):

Marcello Guarino ◽

Salvatore Squillaci ◽

Domenico Reale ◽

Giorgio Micoli

Keyword(s):

Immunohistochemical Staining ◽

Type Iv Collagen ◽

Immunohistochemical Study ◽

Staining Pattern ◽

Complete Loss ◽

Basement Membranes ◽

Sarcomatous Component ◽

Tissue Sections ◽

Type Iv ◽

Frequent Finding

Aims Eight sarcomatoid carcinomas from various anatomical locations were investigated by immunohistochemical staining to laminin, type IV collagen and heparan sulfate proteoglycan, to study the characteristics of basement membranes at the interface between carcinomatous and sarcomatous tissues. Methods Paraffin wax embedded tissue sections from representative tumor samples have been stained with specific antibodies, using the peroxidase-antiperoxidase technique. Results In all cases several interruptions or discontinuities of the basement membrane staining pattern were seen. In 4 cases, larger defects or complete loss of staining was also noted. At these places, the boundaries between carcinomatous and sarcomatous tissue were often blurred. Conclusions Disruption and loss of basement membranes at interface between carcinomatous and sarcomatous tissues is a frequent finding in sarcomatoid carcinomas. These changes could be consistent with an epithelial origin of the sarcomatous component in these tumors by means of an epithelial-mesenchymal conversion mechanism.

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