Pathogenesis of familial hemorrhagic nephritis2017-03-06 14:36
Hereditary nephritis is a basement membrane disease, and collagen IV is the main component of basement membrane, so before discussing the pathogenesis of this disease, we first review the modern understanding of collagen IV structure.
Collagen IV molecules composed of 3 alpha (IV) peptide composition, three helix structure. In addition to the central spiral region, the amino terminal is TS, and the carboxyl terminal is the terminal expanded non collagenous NC1 region. Four collagen molecules amino terminal is connected to two collagen molecules carboxyl terminal, so a net bracket, forming film.
The alpha subunit of collagen IV is known to be of 5 kinds, namely alpha (IV) to alpha 5 (IV), and in recent years, the discovery of the sixth alpha - (IV) 6. The amino acid sequence of alpha 1 (IV), alpha 3 (IV) and alpha (IV) is similar, and the amino acid sequence of alpha (IV), alpha (IV) and alpha 6 (IV) is similar, which can be divided into the following two categories: (), alpha (IV) and alpha (IV) and alpha 5 (IV). It is composed of alpha 1 (IV) and alpha 2 (IV) to form the classic collagen IV molecule, and the type of collagen IV (isoforms) is formed from alpha (IV) to alpha 6 (IV). Known as alpha 1 (IV) and alpha 2 (IV) peptide is widely distributed in a variety of basement membrane, and (IV) alpha 3, alpha 4 (IV) and alpha 5 (IV) peptide were only limited tissue distribution, mainly distributed in GBM, before the lens membrane and the retina (basement membrane due to the difficulty in the inner ear yet, this disease research) the main lesion. Alpha 6 (IV) distribution chain is not yet fully understood, the preliminary data shows it is also limited distribution of collagen alpha chain so the disease variation can be inferred basement membrane in alpha 3 (IV) to alpha 6 (IV).
Previously described, the disease COL4A3 to COL4A6 mutations have been confirmed. In this study, the mutant form of COL4A5 is studied in detail, and it has been reported that there are a few mutations, mutations, deletions, as well as the insertion, duplication and deletion complex, or the complex gene rearrangement of repeat and inversion complex. It has been inferred that the gene mutation leads to enzyme disease, which causes the disorder of collagen synthesis and the growth rate of the enzyme to induce basement membrane disease. Now that genetic diseases can directly lead to abnormal collagen, because play a pathogenic role in all aspects of the mutated DNA can be composed of collagen peptide and peptide in transcription, translation, on. The pathogenesis of the disease may have the following points:
1 Molecular Biology
Type IV collagen is the major component of basement membrane. A single type of collagen chain into the cell to form three helix molecules, and then secrete cells into the extracellular matrix. The mammalian basement membrane contains at least 5 different types of collagen molecules. Similar to other collagen, the collagen chain consists of a major collagen region and a non collagenous region at the carboxyl terminus. The collagen region contains a glycine three -X-Y repeat sequence, X and Y represent a variety of other amino acids. The formation of the three helix of collagen type IV begins with the formation of a disulfide bond in the non collagenous region of the carboxyl terminus of the associated chain. The chain folded into three helix structure and to the amino terminus, this process is similar to the zipper. There are important differences between collagen type IV and interstitial collagen in two aspects, which affect the formation of the macromolecular structure. First, the interstitial collagen lost its carboxyl terminal non collagenous region from the endocrine cell, while the collagen type three helix retained its carboxyl terminal region. Secondly, there is a large number of glycine -X-Y repeats in the collagen chain, which increases the elasticity of the three helix. Type IV collagen three helix forms a network structure through different types of connections:
(1) the end to end connection, that is, the carboxyl terminus of the 2 collagen type three helices.
(2) the effect of the 4 three helices on their amino terminal ends.
(3) a side connection, i.e., the carboxyl terminus of a three helix is attached to the collagen region of the other three helices. These interactions form a flexible, non fibrous, multilateral scaffold. Have cloned 6 genes encoding type IV collagen, respectively encoding alpha 1 (IV) and alpha 2 (IV), COL4A1 and COL4A2 chain gene is located on chromosome 13; (IV) encoding alpha 3 and alpha 4 (IV) COL4A3 and COL4A4 chain gene is located on chromosome 2; (IV) encoding alpha 5 and alpha 6 (IV) long chain genes COL4A5 and COL4A6 on chromosome X; COL4A1 and COL4A2, COL4A3 and COL4A4, COL4A5 and COL4A6 respectively, head to head arrangement, share a bidirectional promoter. These genes are similar, each gene has about 50 exons, the carboxyl terminal region several gene exon 3 'end connected to the encoding. The differences of the carboxyl terminal sequences result in the heterogeneity of antigen specificity, molecular size and charge.
2 mechanisms of renal damage progression
It is unclear how the COL4A5 will eventually lead to renal failure. Although the glomerular basement membrane () of the Alport syndrome is characterized by the absence of alpha 3 (IV), alpha (IV), alpha (IV) chains, many years after the onset of glomerular filtration and selective permeability abnormalities. At the histological level, glomerular basement membrane from Alport syndrome in male children thinned to adult male diffuse thickening of glomerular basement membrane and stratification, need a long period of time, which is in parallel with the natural course of glomerular filtration and selective permeability. Therefore, the basement membrane molecules need to research in this composition during what has changed, the disease process of glomerular sclerosis in what is unique, and what aspects of non Allport syndrome is similar to glomerular change and so on.
Alpha 1 (IV) and alpha 2 (IV)