Dr Diana Blaydon, BSc (Hons), PhD, FHEA

Profile

After obtaining a BSc in Biochemistry from the University of Bath, I worked in the Molecular Genetics Unit at the Institute of Child Health, UCL, during which time I also completed a PhD on the molecular genetics of Usher syndrome (hearing loss in combination with retinitis pigmentosa). In 2004 I joined the Centre for Cell Biology and Cutaneous Research in the Blizard Institute as a postdoc in Professor David Kelsell’s lab, investigating the genetic basis of rare inherited skin diseases. In September 2013 I started working as a non-clinical lecturer in the Blizard Institute.

My research is centred around understanding epidermal barrier function, primarily through the identification of the underlying cause of rare inherited skin disorders, coupled with functional studies to aid understanding of both the underlying disease mechanism as well as the normal biology of the skin.

Teaching

Research

Research Interests:

The epidermis of the skin is a highly specialised stratified epithelium that forms an essential barrier between the body inside and the environment outside, preventing water loss, whilst excluding foreign substances and organisms.

To aid our understanding of the physiology of the epidermal barrier, we perform cell and molecular biology studies on proteins identified in association with rare skin diseases that manifest as barrier defects.

Current research projects build upon recent novel causative genes identified and include:

Understanding the role of the water-channel protein aquaporin-5 (AQP5) in normal and disease skin

We identified mutations in AQP5 as the underlying cause of an autosomal dominant form of diffuse non-epidermolytic palmoplantar keratoderma (NEPPK), a skin disease characterised by thickening of the epidermis on the palms and soles along with an outside-in barrier defect. Prior to this finding, expression of AQP5 in the skin was believed to be restricted to sweat gland cells located in the dermis. The function of AQP5 in epidermal keratinocytes is currently unknown, but the diffuse NEPPK patient phenotype indicates that AQP5 has a role in the establishment and/or maintenance of the epidermal barrier, particularly in the highly specialised epidermis of the palms and soles (palmoplantar) which is exposed to increased levels of mechanical stress.

Understanding palmoplantar skin as a model of stress

Compared to the hairy skin covering the majority of the human body, palmoplantar skin found on our palms and soles is highly specialized to withstand increased levels of mechanical stress. Palmoplantar skin exhibits features associated with stressed skin conditions such as psoriasis, atopic eczema and wound-healing, including: hyperproliferation and constitutive expression of the stress-associated keratins; KRT6, KRT16 and KRT17. However, palmoplantar skin remains largely under-studied and the mechanisms involved in maintaining barrier function in the presence of a ‘stress’ phenotype are not fully understood. We hypothesise that a greater appreciation of the molecular mechanisms employed by the palmoplantar epidermis will improve our understanding of hyperproliferative skin conditions in general.

The role of the iRHOM2-ADAM17 axis in repair and regeneration of the oesophageal barrier

We recently identified mutations in iRHOM2 as the underlying cause of Tylosis, an inherited condition in which affected individuals exhibit thickened skin on palms and soles in combination with lesions of the mucosa in the mouth and oesophagus and an increased lifetime risk for oesophageal cancer. We have shown how iRHOM2, an inactivate member of the Rhomboid family of membrane serine proteases, contributes to repair and regeneration of barrier function in the skin via its regulation of ADAM17 maturation and activity. Tylosis patients exhibit a wound healing defect in both the skin and the oesophagus, another stratified epithelium, highlighting the importance of iRHOM2 in the integrity of both of these barriers. We aim to understand the role of the iRHOM2-ADAM17 axis in repair and regeneration of the normal oesophagus epithelial barrier and investigate if it is compromised in patients with gastro-oesophageal reflux disease (GORD), in which the persistence of a defective oesophageal barrier function appears to be a major underlying factor.

In addition, we continue to seek to identify novel genes associated with rare, monogenic skin disorders through whole exome sequencing or interrogation of whole genome data in the 100,000 Genomes Project.

Publications

Key Publications

Pigors M, Sarig O, Heinz L, Plagnol V, Fischer J, Mohamad J, Malchin N, Rajpopat S, Kharfi M, Le-stringant GG, Sprecher E, Kelsell DP, Blaydon DC (2016) Loss-of-Function Mutations in SERPINB8 Linked to Exfoliative Ichthyosis with Impaired Mechanical Stability of Intercellular Adhesions. Am J Hum Genet; 99(2):430-6.

Blaydon DC, Lind LK, Plagnol V, Linton KJ, Smith FJ, Wilson NJ, McLean WH, Munro CS, South AP, Leigh IM, O'Toole EA, Lundström A, Kelsell DP (2013) Mutations in AQP5, Encoding a Water-Channel Protein, Cause Autosomal-Dominant Diffuse Nonepidermolytic Palmoplantar Keratoderma. Am J Hum Genet; 93(2):330-335.

Blaydon DC, Etheridge SL, Risk JM, Hennies HC, Gay LJ, Carroll R, Plagnol V, McRonald FE, Ste-vens HP, Spurr NK, Bishop DT, Ellis A, Jankowski J, Field JK, Leigh IM, South AP, Kelsell DP (2012) RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome. Am J Hum Genet; 90(2):340-6.

Blaydon DC, Biancheri P, Di WL, Plagnol V, Cabral RM, Brooke MA, van Heel DA, Ruschendorf F, Toynbee M, Walne A, O'Toole EA, Martin JE, Lindley K, Vulliamy T, Abrams DJ, MacDonald TT, Harper JI, Kelsell DP (2011) Inflammatory skin and bowel disease linked to ADAM17 deletion. N Engl J Med; 365(16):1502-8.

Blaydon DC, Ishii Y, O'Toole EA, Unsworth HC, Teh MT, Rüschendorf F, Sinclair C, Hopsu-Havu VK, Tidman N, Moss C, Watson R, de Berker D, Wajid M, Christiano AM, Kelsell DP (2006) R-spondin 4 (RSPO4), a secreted protein implicated in Wnt signalling, is mutated in inherited anonychia. Nat Genet; 38(11):1245-7.

All Publications

Supervision

Primary

• Laura Ramos Del Caño