The Genetic and Functional Basis of Three Inherited Palmoplantar Keratodermas in Human Disease.

PhD ThesisThe ability of cells to respond to stress is fundamental for survival. The palmoplantar epidermis, by its very nature, is subjected to substantial external forces. At birth, the skin at these sites is similar to the skin elsewhere, however, as we expose it to physical stresses such as walking and gripping, it thickens to adapt. The palmoplantar keratodermas (PPKs) are a heterogeneous group of disorders characterised by abnormal thickening of the palmoplantar epidermis. Causative mutations have been identified in a diverse array of genes, such as those encoding the TNFα sheddase, ADAM17, and the water channel protein, Aquaporin 5. Three distinct PPK’s were studied in order to unravel the molecular basis of their associated diseases. The work presented here identifies the palmoplantar and stress-associated Keratin 16 as a novel interacting protein for iRHOM2, and demonstrates that this regulatory relationship contributes to palmoplantar thickness in Tylosis with Oesophageal Cancer. The deep clinical phenotyping of patients with ARVC caused by dominantly inherited mutations in desmoplakin revealed an unreported cutaneous phenotype of PPK and curly hair which may prove useful in the diagnosis of this complex disease. Finally, this Thesis includes the discovery of the first human disease-causing mutation in FAM83G, which presented with a unique phenotype of PPK and abundant curly hair and linked FAM83G to Wnt signaling. By correlating the clinical phenotype with the genotype in each case, and extrapolating from rare monogenic diseases to more common disorders, the PPK’s provide a unique resource in which to study the genetic basis of disease

Tylosis with oesophageal cancer: Diagnosis, management and molecular mechanisms

Research on iRHOM2 in the Kelsell group is funded by an MRC project grant, a MRC Clinical Fellowship (to TM) and a Cancer Research UK program grant

Discovery in Genetic Skin Disease: The Impact of High Throughput Genetic Technologies

The last decade has seen considerable advances in our understanding of the genetic basis of skin disease, as a consequence of high throughput sequencing technologies including next generation sequencing and whole exome sequencing. We have now determined the genes underlying several monogenic diseases, such as harlequin ichthyosis, Olmsted syndrome, and exfoliative ichthyosis, which have provided unique insights into the structure and function of the skin. In addition, through genome wide association studies we now have an understanding of how low penetrance variants contribute to inflammatory skin diseases such as psoriasis vulgaris and atopic dermatitis, and how they contribute to underlying pathophysiological disease processes. In this review we discuss strategies used to unravel the genes underlying both monogenic and complex trait skin diseases in the last 10 years and the implications on mechanistic studies, diagnostics, and therapeutics

Recessive Mutation in FAM83G Associated with Palmoplantar Keratoderma and Exuberant Scalp Hair

To the Editor Palmoplantar keratodermas are a heterogeneous group of disorders characterized by abnormal thickening of the volar epidermis (Blaydon and Kelsell, 2014, Maruthappu et al., 2014). A subset of palmoplantar keratodermas are associated with syndromes linked to other cutaneous features (Betz et al., 2012) and also noncutaneous conditions such as hearing loss, cardiomyopathy, and esophageal cancer (Blaydon Diana et al., 2012, Kelsell et al., 2001). Palmoplantar keratodermas specifically associated with defects in hair development include the desmosomal disorders linked to phenotypes such as woolly hair and alopecia (Brooke et al., 2012). Two adult siblings from a consanguineous family of Pakistani origin, whose parents were first cousins, presented with an autosomal recessively inherited palmoplantar keratoderma, leukonychia, and exuberant curly scalp hair (Figure 1a). Both affected individuals described the progressive development of yellowish thickened scaly skin affecting the palms and soles since 2 years of age, and toenail dystrophy in their teenage years. Examination revealed marked diffuse, verrucous hyperkeratosis with deep fissuring affecting the soles (Figure 1a) and to a lesser extent, the palms. There was no evidence of transgradiens. The toenails were dystrophic with onycholysis and leukonychia was also present, most evident in the finger nails. Onychomycosis was excluded by negative fungal culture. No abnormalities of teeth or sweating were identified. The siblings also described having extremely thick, rapidly growing curly scalp hair since childhood, but without excessive hair growth elsewhere. Neither parent had a similar hair or skin phenotype, and they had no other offspring. Clinical photographs were obtained, and written consent was provided by patients for their publication. Blood samples were collected after written informed consent in adherence with the Declaration of Helsinki principles and approval of the East London and City Health Authority. Whole-exome capture from both siblings was performed using SeqCap EZ Human Exome Library v2.0 (Roche NimbleGen, Madison, WI) and sequenced with 100-bp paired-end reads on the HiSeq 2000 platform (Illumina, San Diego, CA). Resulting reads were mapped to the hg18 human reference genome using the Novoalign alignment tool (Novocraft Technologies Sdn Bhd, Selangor, Malaysia). Sequence variants were called with SAMtools and annotated with ANNOVAR (Wang et al., 2010)