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Volume 12
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10.3390/biomedicines12051060
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Case Report

Novel ATP2A2 Gene Mutation c.118G>A Causing Keratinocyte and Cardiomyocyte Disconnection in Darier Disease

by
Andrea Frustaci
1,*,
Alessandro De Luca
2,
Romina Verardo
1,
Valentina Guida
2,
Maria Alfarano
3,
Camilla Calvieri
3,
Luigi Sansone
4,5,
Matteo Antonio Russo
4 and
Cristina Chimenti
3
1
IRCCS L. Spallanzani, Cellular and Molecular Cardiology Laboratory, 00149 Rome, Italy
2
IRCSS Fondazione Casa Sollievo della Sofferenza, Medical Genetics Division, 71013 San Giovanni Rotondo, Italy
3
Department of Cardiovascular, Respiratory, Nephrologic, Anesthesiologic and Geriatric Sciences, Sapienza University of Rome, 00185 Rome, Italy
4
IRCCS San Raffaele, 00166 Rome, Italy
5
Department of Human Sciences and Promotion of Quality of Life, San Raffaele Open University, 00166 Rome, Italy
*
Author to whom correspondence should be addressed.
Biomedicines 2024, 12(5), 1060; https://doi.org/10.3390/biomedicines12051060
Submission received: 28 February 2024 / Revised: 29 April 2024 / Accepted: 3 May 2024 / Published: 10 May 2024
(This article belongs to the Section Molecular and Translational Medicine)
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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.
Keywords: Darier disease; gene variant; SERCA2; cardiomyocyte disconnection; molecular and cellular rehabilitation Darier disease; gene variant; SERCA2; cardiomyocyte disconnection; molecular and cellular rehabilitation

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MDPI and ACS Style

Frustaci, A.; De Luca, A.; Verardo, R.; Guida, V.; Alfarano, M.; Calvieri, C.; Sansone, L.; Russo, M.A.; Chimenti, C. Novel ATP2A2 Gene Mutation c.118G>A Causing Keratinocyte and Cardiomyocyte Disconnection in Darier Disease. Biomedicines 2024, 12, 1060. https://doi.org/10.3390/biomedicines12051060

AMA Style

Frustaci A, De Luca A, Verardo R, Guida V, Alfarano M, Calvieri C, Sansone L, Russo MA, Chimenti C. Novel ATP2A2 Gene Mutation c.118G>A Causing Keratinocyte and Cardiomyocyte Disconnection in Darier Disease. Biomedicines. 2024; 12(5):1060. https://doi.org/10.3390/biomedicines12051060

Chicago/Turabian Style

Frustaci, Andrea, Alessandro De Luca, Romina Verardo, Valentina Guida, Maria Alfarano, Camilla Calvieri, Luigi Sansone, Matteo Antonio Russo, and Cristina Chimenti. 2024. "Novel ATP2A2 Gene Mutation c.118G>A Causing Keratinocyte and Cardiomyocyte Disconnection in Darier Disease" Biomedicines 12, no. 5: 1060. https://doi.org/10.3390/biomedicines12051060

APA Style

Frustaci, A., De Luca, A., Verardo, R., Guida, V., Alfarano, M., Calvieri, C., Sansone, L., Russo, M. A., & Chimenti, C. (2024). Novel ATP2A2 Gene Mutation c.118G>A Causing Keratinocyte and Cardiomyocyte Disconnection in Darier Disease. Biomedicines, 12(5), 1060. https://doi.org/10.3390/biomedicines12051060

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