Molecular basis of inherited dermatofibromas

Student thesis: Doctoral ThesisDoctor of Philosophy


Dermatofibromas are considered to be common benign fibrotic lumps in the skin, the aetiology of which is poorly understood. I identified two unrelated pedigrees in which there was autosomal dominant transmission of multiple dermatofibromas. Whole exome sequencing revealed a rare shared heterozygous missense variant in F13A1 gene encoding coagulation factor XIII subunit A, a transglutaminase involved in haemostasis, wound healing, tumour growth, and apoptosis. Coincidentally, FXIII-A is one of the key immunohistochemical markers for dermatofibromas. The variant (Lys679Met) has an allele frequency of 0.0002 and is predicted to be a damaging mutation (Polyphen-2 = 1; Mutation taster = 1; CADD = 25.5; DANN = 0.993). Recombinant human Lys679Met FXIII-A demonstrated reduced crosslinking activity in vitro. Of note, treatment of fibroblasts with Lys679Met FXIII-A led to enhanced adhesion, proliferation and type I collagen synthesis. Immunostaining revealed a close association between FXIII-A and α4β1 integrins, and treatment of fibroblasts with α4β1 inhibitors or mutation of the FXIII-A Isoleucine-Leucine-Aspartate-Threonine (ILDT) motif prevented Lys679Met FXIII-A-dependent proliferation and collagen synthesis. These data suggest that the Lys679Met mutation leads to a conformational change in the FXIII-A protein that enhances α4-integrin binding and provide insight into an unexpected role for FXIII-A in the pathobiology of familial dermatofibromas.
Date of Award1 Mar 2020
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorJohn McGrath (Supervisor) & Madeline Parsons (Supervisor)

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