COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets

Abstract

Heterotrimers composed of collagen type IV alpha 1 (COL4A1) and alpha 2 (COL4A2) constitute one of the most abundant components of nearly all basement membranes. Accordingly, mutations in COL4A1 or COL4A2 are pleiotropic and contribute to a broad spectrum of disorders, including myopathy, glaucoma and hemorrhagic stroke. Here, we summarize the contributions of COL4A1 and COL4A2 mutations in human disease, integrate knowledge gained from model organisms and evaluate the implications for pathogenic mechanisms and therapeutic approaches.

Figure 1.

Distribution of COL4A1 and COL4A2 mutations in schematics of human and mouse proteins. The Col4a1 and Col4a2 genes are transcribed from a shared, bidirectional promoter. Mature proteins are composed of three distinct domains: 7S, collagenous and non-collagenous (NC1). Mutations identified in humans and in mice are indicated above and below the schematics, respectively, with mutations causing HANAC Syndrome (hereditary angiopathy with nephropathy, aneurysms and muscle cramps) shown in red. Probable pathogenic human mutations, defined as displaying an unambiguous familial inheritance pattern, are in bold while other putative pathogenic human mutations are in plain text.

Figure 2.

Schematic representation of type IV collagen biosynthesis and potential sites for pathogenic insults. (A) Collagen proteins undergo extensive post-translational modifications and assemble into heterotrimers for secretion into the ECM where they polymerize into a network and interact with other extracellular and membrane bound molecules [LH, lysyl hydroxylase; PH, prolyl hydroxylase; PDI, protein disulphide isomerase; S, secreted protein, acidic, cysteine-rich (SPARC); H, heat shock protein 47 (HSP47)]. (B) Assuming random assembly within the ER of cells heterozygous for COL4A1 mutations, 25% of heterotrimers will be normal, 50% of heterotrimers will incorporate one mutant COL4A1 protein and 25% of heterotrimers will incorporate two mutant COL4A1 proteins. Normal heterotrimers (left) are presumed to be secreted, while heterotrimers containing two mutant proteins (right) are not. It is unknown if heterotrimers with one normal and one mutant COL4A1 are secreted. (Heterozygous mutations in COL4A2 would produce only the first two classes of heterotrimers at 50% each.) The primary pathogenic insult may be intracellular (cytotoxic accumulation of mutant heterotrimers) or extracellular (either the presence of mutant heterotrimers or the deficiency of heterotrimers in basement membranes). Either putative extracellular insult could directly or indirectly alter interactions with signaling molecules such as BMPs (represented as blue circles) or cell-surface receptors such as integrins (represented as grey structures), which can in turn lead to autocrine or paracrine intracellular signaling defects.