Collagen IV is a main component of basement membranes. COL4A1 gene encodes for the alpha-1(IV) chain, that is an ubiquitously expressed isoform of collagen IV. Mutations of COL4A1 were described in 2005 in patients presenting with autosomal dominant cerebral small vessel disease, sometimes associated with eye defects. We have characterized in 2007 a distinct phenotypic presentation, named HANAC (an acronyme for Hereditary Angiopathy, Nephropathy, Aneurysm and Cramps), that associates renal defects (multicystic kidney disease and hematuria), muscle cramps and retinal arteriolar tortuosity (Plaisier E et al, NEJM, 2007). COL4A1 mutations in HANAC are closely localised in a 30 amino-acid region of the protein that contains integrin-binding sites, thus suggesting a genotype-phenotype correlation.
To get insight into the pathophysiology of HANAC, and more generally, to further understand the role of collagen IV in the kidney, vessel and muscles, we have generated HANAC Col4a1 mutant mouse models. The analysis of the renal phenotype of these animals reveals a potential important developmental role of the Col4a1 protein during glomerulogenesis. In addition, HANAC mutant mice show a vascular phenotype that highlights a functional role of collagen IV in the vessel wall, in addition to its mechanical properties in basement membranes. These mutant animals provide important clues regarding the pathogenicity of Col4a1 missense mutations observed in patients, by inducing endoplasmic reticulum stress. These animals are currently used to test different therapeutic approaches.