Discovery and translation in rare and common inflammatory childhood disease
Evolutionary Cell and Developmental Biology (Zoology)
Final Report Abstract
Atopic eczema (AE) and other inflammatory skin disease are one of the most challenging conditions in dermatology and are associated with considerable clinical variability and complex disease mechanisms. Using modern DNA sequencing techniques, i.e. whole exome sequencing, and cell-biological studies, we aimed to determine the genetic and molecular basis of both common and rare inflammatory skin diseases in children. One part of the project focused on the identification of new risk genes that contribute to the development and severity of AE, which is one of the most prevalent chronic inflammatory skin conditions in children. In particular, we studied large Bangladeshi families residing in East London, UK, where siblings were affected with severe AE and other AE associated conditions including asthma, hay fever and food allergies. Using whole exome sequencing and a novel bioinformatics approach where we looked at an enrichment of rare changes in parts of the DNA that encode for proteins. This analysis revealed that the filaggrin gene (FLG), which was previously associated with AE, carried the highest number of gene variants. Moreover, our enrichment strategy led to the identification of potential high risk changes in new genes that have not yet been linked to AE. These include the MTF1 gene, which is an important regulator of heavy metal balances in the cells and the ORM2 gene, which represents a critical regulator of anti-inflammation. In addition, to the Bangladeshi AE patient cohort, we investigated other AE groups with European, African-American, and Singapore Chinese ancestry and the Bangladeshi AE-associated risk genes were, in part, also identified at high frequency in the different populations, suggesting that some AE risk variants are shared between populations while others maybe ethnicity-specific. In the future we plan to investigate the newly identified disease molecules in normal and AE skin biology. In the second study, we identified three unrelated families with genetic changes in the SERPINB8 gene, in association with a rare form of exfoliative ichthyosis, which is characterized by mild peeling of the skin mainly on hands and feet. Microscopic analysis of a skin biopsy from one of the patients showed that the integrity of the major cell types in the skin, the keratinocytes, is partly impaired. Moreover, the protein levels of SERPINB8 were markedly reduced in the patient’ skin. As the role of SERPINB8, which encodes a protease inhibitor, in the skin is largely unknown, we performed cell-biological studies where we deactivated SERPINB8 in a keratinocyte cell line. We demonstrated that in the absence of the protein, the cellular attachment is impaired, particularly when cells are subjected to mechanical stress. In addition, we demonstrated that levels of desmosomal proteins, which seal the cells together, were increased in SERPINB8-deficient cells. In conclusion, we report a new gene, SERPINB8, which is linked to mild peeling of the skin and provide evidence that SERPINB8 contributes to the mechanical stability of intercellular bonds in the upper part of the skin. Taken together, we have identified novel disease molecules associated with both common and rare skin diseases. Understanding the role of the new proteins in the organization of the skin and in inflammation, in particular for AE and other associated atopic diseases, will open new possibilities for new therapeutic strategies for treatment of these complex disorders.
Publications
- Cover image: Unpeeling the layers of harlequin ichthyosis. Br J Dermatol. Vol 174 Issue 5, May 2016, Pages 1160-1161
Harris AG, Choy C, Pigors M, Kelsell DP, Murrell DF
(See online at https://doi.org/10.1111/bjd.14469) - Loss-of-function mutations in SERPINB8 linked to exfoliative ichthyosis with impaired mechanical stability of intercellular adhesions. Am J Hum Genet. AJHG Vol 99, Issue 2, 4 August 2016, Pages 430-436
Pigors M, Sarig O, Heinz L, Plagnol V, Fischer J, Mohamad J, Rajpopat S, Kharfi M, Lestringant GG, Sprecher E, Kelsell DP, Blaydon DC
(See online at https://doi.org/10.1016/j.ajhg.2016.06.004)
