• collagen disease

Type IV collagen is a network-forming collagen found primarily in the basal lamina and constitutes a major structural component of basement membranes. There are six genes in human encoding alpha subunits of type IV collagen (COL4A1 though COL4A6); there are two in Drosophila, Dmel\Col4a1 and Dmel\vkg. As might be expected, defects affecting basement membranes have widespread effects. The six human genes are associated with an array of diseases, including angiopathies, kidney disease, and deafness, as well as syndromes with combinations of disease phenotypes. Using Dmel\Col4a1, two aspects of type IV collagenopathy have been investigated in flies: myopathy and kidney disease. Loss-of-function alleles, dominant temperature-sensitive alleles, RNAi targeting constructs, alleles caused by insertional mutagenesis, and amorphic alleles created by targeted recombination have been generated for Col4a1.

None of the human collagen type IV alpha genes has been introduced into flies.

Animals homozygous for amorphic mutations of Dmel\Col4a1 typically die during the embryonic stage. Dominant temperature-sensitive alleles have been used to characterize phenotypes relevant to human type IV collagenopathies. Muscle phenotypes have been characterized in myofibers of the oviduct: muscle fibers are observed to detach laterally from each other with focal splitting of the basement membrane; the basement membrane surrounding the myofibers appeared distorted, thinned, or absent. Phenotypes of Malpighian tubules, which perform many of the functions of the human kidney, indicate that Col4a1 mutations result in mitochondrial and other defects in tubule epithelial cells, which leads to impaired secretory function of the Malpighian tubules. Aberrant posttranslational protein modifications may play a role in tubule epithelial degeneration, driven by higher levels of peroxynitrite observed in mutant animals. Physical and genetic interactions have been described for Dmel\Col4a1; see below and in the Col4a1 gene report.

[updated Apr. 2019 by FlyBase; FBrf0222196]