Alport Syndrome and Basement Membrane Collagen

ABSTRACT

• Alport syndrome is a progressive hereditary kidney disease characterized by hematuria, and often associated with extrarenal complications, such as sensorineural hearing loss and ocular abnormalities. By electron microscopy ultrastructural changes, including thinning, thickening, and splitting, can be seen in the glomerular basement membrane (GBM). Alport syndrome is mainly inherited as an X-linked dominant trait (MIM 301050) with mutations in the type IV collagen α5 chain gene (COL4A5), but both autosomal recessive (MIM 203780) and dominant forms also exist. Autosomal Alport syndrome is caused by mutations in the COL4A3 and COL4A4 genes encoding the type IV collagen α3 and α4 chains, respectively. Additionally, numerous deletions involving the 5′ ends of both the COL4A6 gene and the adjacent COL4A5 gene have been reported to cause a rare disorder, diffuse leiomyomatosis, that is associated with Alport syndrome (MIM 308940, 303631). A minority of Alport syndrome patients develop anti-GBM nephritis involving the transplanted allograft.

• Basement membranes are thin, extracellular, sheet-like structures that separate cells of organized tissues from the interstitial connective tissue. The major complications of Alport syndrome—hematuria and proteinuria—are caused by structural alterations and consequent malfunction of the glomerular filtration barrier, especially glomerular basement membrane, a major component of the glomerular filtration barrier. The molecular structure of the GBM is much the same as that of basement membranes in other tissues. The major structural component is type IV collagen that forms a tightly cross-linked network in which a less dense laminin network is connected via entactin (nidogen) molecules.

• Different triple-helical type IV collagen molecules are composed of six genetically distinct α-chains, namely α1(IV), α2(IV), α3(IV), α4(IV), α5(IV), or α6(IV). Each type IV collagen α-chain contains a long collagenous domain, a short noncollagenous N-terminus, and a noncollagenous domain (NC1) at the C-terminus. Type IV collagen molecules self-assemble into a complex network structure via C-terminal NC1 domains forming dimers, and at the N-termini forming tetramers. The molecular composition of different type IV collagen networks varies from tissue to tissue.

• Type IV collagen genes are very large, the smallest one having 46 exons. An interesting feature is that the six genes are located pair-wise in three different chromosomes, sharing a common bidirectional promoter.

• About 300 mutations have been reported in Alport syndrome patients in the COL4A3, COL4A4, and COL4A5 genes. Different mutations cause different phenotypes, but it is difficult to predict the consequences of a certain mutation, because deletion of a whole gene does not necessarily produce a more severe phenotype than does an amino acid substitution. Immunohistologic studies of tissues from Alport syndrome patients demonstrate the existence of different α-chain networks in different tissues. Thus, differential pattern of staining in skin sections may be used to distinguish between X-linked and autosomal recessive forms of Alport syndrome.

• Alport syndrome, which primarily affects the renal glomeruli, is an attractive disease target for gene therapy.

CLINICAL FEATURES

Clinical Findings

In 1927, Professor ...