Deletions in the COL4A5 collagen gene in X-linked Alport syndrome. Characterization of the pathological transcripts in nonrenal cells and correlation with disease expression.

Antignac, Corinne; Knebelmann, Bertrand; Drouot, Laurent; Gros, François; Deschênes, Georges; Hors-Cayla, M C; Zhou, Jing; Tryggvason, Karl; Grünfeld, Jean‐Pierre; Broyer, M.

doi:10.1172/jci117073

Cited by 77 publications

(35 citation statements)

References 31 publications

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“…X-linked transmission was demonstrated on the basis of pedigree structure (5 patients), linkage analysis (3 patients), and/or the demonstration of a COL4A5 mutation (4 patients) which has been previously reported. 12,13 Immunohistology Antibodies Commercially available affinity-purified antibodies raised against pepsin-digested human placenta type IV collagen were obtained from Pasteur-Lyon (Lyon, France). They recognize the collagenous domain of the [␣1(IV)2 ␣2(IV)] collagen protomer.…”

Section: Patientsmentioning

confidence: 99%

“…6 -11 COL4A5 mutations lead to the most common form of AS which is X-linked, whereas COL4A3 and COL4A4 mutations are responsible for the autosomal recessive forms. [12][13][14][15][16][17][18][19] The primary structure of the six ␣(IV) chains is very similar. Each is characterized by an ϳ25-residue noncollagenous domain at the amino terminus, an ϳ1400 residue collagenous domain of Gly-X-Y repeats (in which X is frequently proline and Y is frequently hydroxyproline), that forms, in association with two other chains, the triple helix, and an ϳ230-residue noncollagenous (NC1) domain at the carboxyl terminus.…”

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confidence: 99%

“…28 -31 The presence of cysteine-rich ␣3(IV) and ␣4(IV) chains, forming with ␣5(IV) a network containing loops and supercoiled triple helices stabilized by disulfide bonds between the chains, seems to be important with regards to the longterm stability of the GBM and its role as a filter. 26,32 Despite the increasing number of AS mutations reported in the literature [12][13][14][15][16][17][18][19] and the existence of AS animal models, [33][34][35][36][37] several questions regarding the consequences of AS mutations on the collagen organization within the GBM and the mechanisms responsible for the progressive development of AS nephropathy remain unanswered. A striking feature observed in the majority of AS is the absence of all three ␣3(IV), ␣4(IV), and ␣5(IV) chains within the GBM although only one of these chains is actually mutated.…”

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confidence: 99%

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Glomerular Expression of Type IV Collagen Chains in Normal and X-Linked Alport Syndrome Kidneys

Heidet

Cai

Guicharnaud

et al. 2000

The American Journal of Pathology

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Alport syndrome is an inherited nephropathy characterized by alterations of the glomerular basement membrane because of mutations in type IV collagen genes. COL4A5 mutations, causing X-linked Alport syndrome, frequently result in the loss of the ␣5 chains of type IV collagen in basement membranes. This is associated with the absence of the ␣3(IV) and ␣4(IV) chains and increased amounts of ␣1(IV) and ␣2(IV) in glomerular basement membranes. The mechanisms resulting in such a configuration are still controversial and are of fundamental importance for understanding the pathology of the disease and for considering gene therapy. In this article we studied, for the first time, type IV collagen expression in kidneys from X-linked Alport syndrome patients, using in situ hybridization and immunohistochemistry. We show that, independent of the type of mutation and of the level of COL4A5 transcription, both COL4A3 and COL4A4 genes are actively transcribed in podocytes. Moreover, using immunofluorescence amplification, we were able to demonstrate that the ␣3 chain of type IV collagen was present in the podocytes of all patients. Finally, the ␣1(IV) chain, which accumulates within glomerular basement membranes, was found to be synthesized by mesangial/endothelial cells. These results strongly suggest that, contrary to what has been found in dogs affected with X-linked Alport syndrome, there is no transcriptional co-regulation of COL4A3, COL4A4, and COL4A5 genes in humans, and that the absence of ␣3(IV) to ␣5(IV) in glomerular basement membranes in the patients results from events downstream of transcription, RNA processing, and protein synthesis.

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Section: Patientsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Glomerular Expression of Type IV Collagen Chains in Normal and X-Linked Alport Syndrome Kidneys

Heidet

Cai

Guicharnaud

et al. 2000

The American Journal of Pathology

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“…About 80% of the affected families exhibit Xlinked inheritance of mutations in the COL4A5 gene (13,14), while some of the remainder inherit autosomal recessive mutations in ␣3(IV) and ␣4(IV) chains (15,16). To date, over 200 mutations have been found in the COL4A5 gene (13,14,17,18).…”

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confidence: 99%

Glomerular Basement Membrane

Gunwar¹,

Ballester²,

Noelken³

et al. 1998

Journal of Biological Chemistry

208

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Glomerular basement membrane (GBM) plays a crucial function in the ultrafiltration of blood plasma by the kidney. This function is impaired in Alport syndrome, a hereditary disorder that is caused by mutations in the gene encoding type IV collagen, but it is not known how the mutations lead to a defective GBM. In the present study, the supramolecular organization of type IV collagen of GBM was investigated. This was accomplished by using pseudolysin (EC 3.4.24.26) digestion to excise truncated triple-helical protomers for structural studies. Two distinct sets of truncated protomers were solubilized, one at 4°C and the other at 25°C, and their chain composition was determined by use of monoclonal antibodies. The 4°C protomers comprise the ␣1

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“…Na realidade o defeito primário está associado a herança ligada ao cromossomo X, em 85% dos casos (10) como resultado de mutações do gene COL 4A5 (10)(11) . Estima-se que 2% a 5% dos casos do sexo masculino e 1% do sexo feminino, com insuficiência renal crônica (IRC) seja devido a Síndrome de Alport cuja prevalên-cia varia de 1:5000 a 1:10000 nos EUA, no entanto estimativas mundiais ainda não são possíveis de serem determinadas (4) .…”

Section: I S C U S S ã Ounclassified