Coagulation Factor XIII-A Subunit Missense Mutation in the Pathobiology of Autosomal Dominant Multiple Dermatofibromas

Chavalit Supsrisunjai, Chao Kai Hsu, Magdalene Michael, Cédric Duval, John Y.W. Lee, Hsing San Yang, Hsin Yu Huang, Thitiwat Chaikul, Alexandros Onoufriadis, Roberto A. Steiner, Robert A.S. Ariëns, Ofer Sarig, Eli Sprecher, Marina Eskin-Schwartz, Curt Samlaska, Michael A. Simpson, Eduardo Calonje, Maddy Parsons, John A. McGrath

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Dermatofibromas are common benign skin lesions, the etiology of which is poorly understood. We 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 the F13A1 gene encoding factor XIII subunit A (FXIII-A), a transglutaminase involved in hemostasis, wound healing, tumor growth, and apoptosis. The variant (p.Lys679Met) has an allele frequency of 0.0002 and is predicted to be a damaging mutation. Recombinant human Lys679Met FXIII-A demonstrated reduced fibrin crosslinking activity in vitro. Of note, the treatment of fibroblasts with media containing Lys679Met FXIII-A led to enhanced adhesion, proliferation, and type I collagen synthesis. Immunostaining revealed co-localization between FXIII-A and α4β1 integrins, more prominently for Lys679Met FXIII-A than the wild type. In addition, both the α4β1 inhibitors and the mutation of the FXIII-A Isoleucine-Leucine-Aspartate-Threonine (ILDT) motif prevented Lys679Met FXIII-A-dependent proliferation and collagen synthesis of fibroblasts. Our data suggest that the Lys679Met mutation may lead to a conformational change in the FXIII-A protein that enhances α4-integrin binding and provides insight into an unexpected role for FXIII-A in the pathobiology of familial dermatofibroma.

Original languageEnglish
Pages (from-to)624-635.e7
JournalJournal of Investigative Dermatology
Volume140
Issue number3
DOIs
Publication statusPublished - 2020 Mar

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

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