Institute of Cardiovascular and Medical Sciences

Principal Investigator

Collaborators

The role of the basement membrane and collagen IV in human disease

Cells within the body are surrounded by a structural support called the extracellular matrix. This matrix is composed of proteins that are produced and correctly folded inside cells and then exported into this matrix. The human body contains many different types of collagen protein that make up 25-30% of total body mass. Two type IV collagens, COL4A1 and COL4A2, are the predominant collagens found in a special structure within the extracellular matrix, called the basement membrane, which provides structural support to the wall of blood vessels. These collagens are produced from two genes named COL4A1 and COL4A2, and bind each other to form a complex. Mutations in the COL4A2 or COL4A1 genes result in bleeding from blood vessels in the brain (a form of stroke). Patients also frequently suffer from eye and kidney disease. Using a combination of mouse models with Col4a1 mutations and patient cells, our research investigates how these mutations result in the different diseases with the aim of developing treatment options. Whilst mutations in collagen type IV are thought to be rare, by studying how they lead to stroke, eye and kidney disease we may learn more about common forms of diseases such as chronic kidney disease and stroke, which is one of the most common causes of death and disability in Western society.

Basement membranes are specialised extracellular matrix structures that compartmentalise tissues, provides structural support and influence cell behaviour. Collagen IV is a major basement membrane component and recently we and others have found that COL4A1 and COL4A2 (collagen IV alpha chains 1 and 2) mutations affect mainly the eye, kidney and vasculature, as observed in HANAC syndrome (Hereditary angiopathy and nephropathy with aneurysm and cramps). The cerebrovascular phenotypes can include paediatric and adult haemorrhagic stroke, adult small vessel disease and lacunar infarcts.

Haemorrhagic stroke accounts for 10-15% of all stroke cases, the leading cause of disability in Europe, and can lead to a wide spectrum of clinical consequences including porencephaly, which is a rare central nervous system disease characterised by white matter lesions and degenerative cavities. While multiple factors, including vascular malformations, are associated with stroke, many of the genetic causes and disease mechanisms remain unknown.

Using mouse models we have shown that Col4a1 mutations in mice result in both basement membrane (BM) defects and endoplasmic reticulum (ER) stress, which can be caused by mutations in secreted proteins that lead to misfolding of these proteins in the ER. However the relative contribution of BM defects and ER-stress to the pathological mechanisms remains unknown. Using a combination of mouse models and tissue culture, my lab aims to analyse the role of collagen type IV in human disease, establish the mechanisms underlying the different pathologies with the long term aim of identifying therapeutic avenues. This will not only inform on collagen IV diseases but may also shed light on mechanisms underlying common forms of stroke, eye and kidney disease.

Selected Publications

  1. Taylor SH, Al-Youha S, Van Agtmael T, Lu Y, Wong J, McGrouther DA, Kadler KE.  Tendon is covered by a basement memberane epithelium that is required for cell retention and the prevention of adhesion formation.  PLoS One 2011;6:e163337.
  2. Van Agtmael T, Bruckner-Tuderman L.  Basement membranes and human disease.  Cell Tissue Res 2010;339(1):167-88.
  3. Van Agtmael T, Bailey MA, Schlotzer-Schrehardt U, Craigie E, Jackson IJ, Brownstein DG, Megson IL, Mullins JJ.  Col4a1 mutation in mice causes defects in vascular function and low blood pressure associated with reduced red blood cell volume.  Human Molecular Genetics 2010;357:2687-2695.
  4. Alamowitch S, Plaisier E, Favrole P, Prost C, Chen Z, Van Agtmael T, Marro B, Ronco P.  Cerebrovascular disease related to COL4A1 mutations in HANAC syndrome.  Neurology 2009;73:1873-82.
  5. Plaiser E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, Marro B, Desmettre T, Cohen SY, Roullet E, Dracon M, Fardeau M, Van Agtmael T, Kerjaschki D, Antignac C, Ronco P.  COL4A1 mutations and heredity angiopathy, nephropathy, aneurysms, and muscle cramps.  N Engl J Med 2007;357:2687-95.
  6. Van Agtmael T.  Dominiant mutations of Col4a1 result in basement membrane defects which lead to anterior segment dysgenesis and glomerulopathy.  Human Molecular Genetics 2005;14:3161-3168.