Darier disease (DD) is an autosomal dominant disorder due to pathogenic variants of the ATP2A2 gene that causes an isolated skin manifestation based on keratinocyte disconnection and apoptosis. Systemic manifestations of DD have not been demonstrated so far, although a high incidence of neuropsychiatric syndromes suggests an involvement of the central nervous system. We report that the pathogenic ATP2A2 gene variant c.118G>A may cause cardiac involvement in patients with DD, consisting of keratinocyte and cardiomyocyte disconnection. Their common pathologic pathway, still unreported, was documented by both skin and left ventricular endomyocardial biopsies because cardiac dilatation and dysfunction appeared several decades after skin manifestations. Keratinocyte disconnection was paralleled by cardiomyocyte separation at the lateral junction. Cardiomyocyte separation was associated with cell disarray, sarcoplasmic reticulum dilatation, and increased myocyte apoptosis. Clinically, hyperkeratotic skin papules are associated with chest pain, severe muscle exhaustion, and ventricular arrhythmias that improved following administration of aminophylline, a phosphodiesterase inhibitor enhancing SERCA2 protein phosphorylation. Cardiac pathologic changes are similar to those documented in the skin, including cardiomyocyte disconnection that promotes precordial pain and cardiac arrhythmias. Phosphodiesterase inhibitors that enhance SERCA2 protein phosphorylation may substantially attenuate the symptoms.

Novel ATP2A2 gene mutation C.118g>A causing keratinocyte and cardiomyocyte disconnection in darier disease / Frustaci, Andrea; De Luca, Alessandro; Verardo, Romina; Guida, Valentina; Alfarano, Maria; Calvieri, Camilla; Sansone, Luigi; Russo, Matteo Antonio; Chimenti, Cristina. - In: BIOMEDICINES. - ISSN 2227-9059. - 12:5(2024). [10.3390/biomedicines12051060]

Novel ATP2A2 gene mutation C.118g>A causing keratinocyte and cardiomyocyte disconnection in darier disease

Frustaci, Andrea
;
Verardo, Romina;Guida, Valentina;Alfarano, Maria;Calvieri, Camilla;Sansone, Luigi;Russo, Matteo Antonio;Chimenti, Cristina
2024

Abstract

Darier disease (DD) is an autosomal dominant disorder due to pathogenic variants of the ATP2A2 gene that causes an isolated skin manifestation based on keratinocyte disconnection and apoptosis. Systemic manifestations of DD have not been demonstrated so far, although a high incidence of neuropsychiatric syndromes suggests an involvement of the central nervous system. We report that the pathogenic ATP2A2 gene variant c.118G>A may cause cardiac involvement in patients with DD, consisting of keratinocyte and cardiomyocyte disconnection. Their common pathologic pathway, still unreported, was documented by both skin and left ventricular endomyocardial biopsies because cardiac dilatation and dysfunction appeared several decades after skin manifestations. Keratinocyte disconnection was paralleled by cardiomyocyte separation at the lateral junction. Cardiomyocyte separation was associated with cell disarray, sarcoplasmic reticulum dilatation, and increased myocyte apoptosis. Clinically, hyperkeratotic skin papules are associated with chest pain, severe muscle exhaustion, and ventricular arrhythmias that improved following administration of aminophylline, a phosphodiesterase inhibitor enhancing SERCA2 protein phosphorylation. Cardiac pathologic changes are similar to those documented in the skin, including cardiomyocyte disconnection that promotes precordial pain and cardiac arrhythmias. Phosphodiesterase inhibitors that enhance SERCA2 protein phosphorylation may substantially attenuate the symptoms.
2024
darier disease; SERCA2; cardiomyocyte disconnection; gene variant; molecular and cellular rehabilitation
01 Pubblicazione su rivista::01a Articolo in rivista
Novel ATP2A2 gene mutation C.118g>A causing keratinocyte and cardiomyocyte disconnection in darier disease / Frustaci, Andrea; De Luca, Alessandro; Verardo, Romina; Guida, Valentina; Alfarano, Maria; Calvieri, Camilla; Sansone, Luigi; Russo, Matteo Antonio; Chimenti, Cristina. - In: BIOMEDICINES. - ISSN 2227-9059. - 12:5(2024). [10.3390/biomedicines12051060]
File allegati a questo prodotto
File Dimensione Formato  
Frustaci_Novel_2024.pdf

accesso aperto

Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Creative commons
Dimensione 4.54 MB
Formato Adobe PDF
4.54 MB Adobe PDF

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1727521
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 0
  • ???jsp.display-item.citation.isi??? 0
social impact