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Epidermal growth factor receptor inhibition leads to cellular phenotype correction of DSP-mutated keratinocytes.
Andrei, Daniela; Bremer, Jeroen; Kramer, Duco; Nijenhuis, Albertine M; van der Molen, Marije; Diercks, Gilles F H; van den Akker, Peter C; Vermeer, Mathilde C S C; van der Meer, Peter; Bolling, Maria C.
Afiliación
  • Andrei D; Department of Dermatology, Expertise Center for Blistering Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
  • Bremer J; Department of Dermatology, Expertise Center for Blistering Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
  • Kramer D; Department of Dermatology, Expertise Center for Blistering Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
  • Nijenhuis AM; Department of Dermatology, Expertise Center for Blistering Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
  • van der Molen M; Department of Dermatology, Expertise Center for Blistering Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
  • Diercks GFH; Department of Pathology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
  • van den Akker PC; Department of Genetics, Expertise Center for Blistering Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
  • Vermeer MCSC; Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
  • van der Meer P; Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
  • Bolling MC; Department of Dermatology, Expertise Center for Blistering Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Exp Dermatol ; 33(3): e15046, 2024 Mar.
Article en En | MEDLINE | ID: mdl-38509711
ABSTRACT
Desmoplakin (DSP) is a desmosomal component expressed in skin and heart, essential for desmosome stability and intermediate filament connection. Pathogenic variants in the DSP gene encoding DSP, lead to heterogeneous skin, adnexa and heart-related phenotypes, including skin fragility, woolly hair (WH), palmoplantar keratoderma (PPK) and arrhythmogenic/dilated cardiomyopathy (ACM/DCM). The ambiguity of computer-based prediction analysis of pathogenicity and effect of DSP variants, indicates a necessity for functional analysis. Here, we report a heterozygous DSP variant that was not previously described, NM_004415.4c.3337C>T (NM_004415.4(NP_004406.2)p.(Arg1113*)) in a patient with PPK, WH and ACM. RNA and protein analysis revealed ~50% reduction of DSP mRNA and protein expression. Patient's keratinocytes showed fragile cell-cell connections and perinuclear retracted intermediate filaments. Epidermal growth factor receptor (EGFR) is a transmembrane protein expressed in the basal epidermal layer involved in proliferation and differentiation, processes that are disrupted in the development of PPK, and in the regulation of the desmosome. In skin of the abovementioned patient, evident EGFR upregulation was observed. EGFR inhibition in patient's keratinocytes strongly increased DSP expression at the plasma membrane, improved intermediate filament connection with the membrane edges and reduced the cell-cell fragility. This cell phenotypic recovery was due to a translocation of DSP to the plasma membrane together with an increased number of desmosomes. These results indicate a therapeutic potential of EGFR inhibitors for disorders caused by DSP haploinsufficiency.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Queratodermia Palmoplantar / Desmoplaquinas / Receptores ErbB / Enfermedades del Cabello Límite: Humans Idioma: En Revista: Exp Dermatol Asunto de la revista: DERMATOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Dinamarca
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Queratodermia Palmoplantar / Desmoplaquinas / Receptores ErbB / Enfermedades del Cabello Límite: Humans Idioma: En Revista: Exp Dermatol Asunto de la revista: DERMATOLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Dinamarca