Basement membranes are highly specialized extracellular matrices that act as dynamic and versatile signaling platforms to regulate tissue development, function, and repair. COL4A1 and COL4A2 are major component of virtually basement membranes. They evolved 750 million years ago along with the earliest multicellular organisms and have been integrated into diverse fundamental biological processes as time and evolution shaped the animal kingdom. Consequently, mutations in these two genes result in multi-system disorders with ambiguous and overlapping boundaries. Our work suggests that the complexity and spectrum of disease severity reflect the simultaneous interplay and integration of multiple cellular pathways and processes. Treatments and therapies are likely to be as varied as the phenotypes. Understanding tissue-specific pathology and the underlying molecular mechanism is the present challenge and personalized medicine will rely upon understanding how a given mutation impacts diverse cellular functions.
COL4A1 and COL4A2 form heterotrimers that constitute a major component of nearly all basement membranes and COL4A1 /COL4A2 mutations lead to a multisystem syndrome marked by clinical heterogeneity and variable expressivity, generally characterized by the presence of cerebrovascular disease with variable ocular, neurological, renal and muscular involvement. Since I joined the lab, I have been using a combination of genetic tools and preclinical mouse models to identify and characterize different pathologies caused byCOL4A1/COL4A2 mutations, elucidate the pathogenic mechanisms leading to disease, and test the efficacy of potential therapeutic interventions.