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A rare loss-of-function genetic mutation suggest a role of dermcidin deficiency in hidradenitis suppurativa pathogenesis

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with a multifactorial aetiology that involves a strict interplay between genetic factors, immune dysregulation and lifestyle. Familial forms represent around 40% of total HS cases and show an autosomal dominant mode of inheritance...

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Autores principales: Tricarico, Paola Maura, Gratton, Rossella, dos Santos-Silva, Carlos André, de Moura, Ronald Rodrigues, Ura, Blendi, Sommella, Eduardo, Campiglia, Pietro, Del Vecchio, Cecilia, Moltrasio, Chiara, Berti, Irene, D’Adamo, Adamo Pio, Elsherbini, Ahmed M. A., Staudenmaier, Lena, Chersi, Karin, Boniotto, Michele, Krismer, Bernhard, Schittek, Birgit, Crovella, Sergio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9760663/
https://www.ncbi.nlm.nih.gov/pubmed/36544771
http://dx.doi.org/10.3389/fimmu.2022.1060547
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author Tricarico, Paola Maura
Gratton, Rossella
dos Santos-Silva, Carlos André
de Moura, Ronald Rodrigues
Ura, Blendi
Sommella, Eduardo
Campiglia, Pietro
Del Vecchio, Cecilia
Moltrasio, Chiara
Berti, Irene
D’Adamo, Adamo Pio
Elsherbini, Ahmed M. A.
Staudenmaier, Lena
Chersi, Karin
Boniotto, Michele
Krismer, Bernhard
Schittek, Birgit
Crovella, Sergio
author_facet Tricarico, Paola Maura
Gratton, Rossella
dos Santos-Silva, Carlos André
de Moura, Ronald Rodrigues
Ura, Blendi
Sommella, Eduardo
Campiglia, Pietro
Del Vecchio, Cecilia
Moltrasio, Chiara
Berti, Irene
D’Adamo, Adamo Pio
Elsherbini, Ahmed M. A.
Staudenmaier, Lena
Chersi, Karin
Boniotto, Michele
Krismer, Bernhard
Schittek, Birgit
Crovella, Sergio
author_sort Tricarico, Paola Maura
collection PubMed
description Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with a multifactorial aetiology that involves a strict interplay between genetic factors, immune dysregulation and lifestyle. Familial forms represent around 40% of total HS cases and show an autosomal dominant mode of inheritance of the disease. In this study, we conducted a whole-exome sequence analysis on an Italian family of 4 members encompassing a vertical transmission of HS. Focusing on rare damaging variants, we identified a rare insertion of one nucleotide (c.225dupA:p.A76Sfs*21) in the DCD gene encoding for the antimicrobial peptide dermcidin (DCD) that was shared by the proband, his affected father and his 11-years old daughter. Since several transcriptome studies have shown a significantly decreased expression of DCD in HS skin, we hypothesised that the identified frameshift insertion was a loss-of-function mutation that might be associated with HS susceptibility in this family. We thus confirmed by mass spectrometry that DCD levels were diminished in the affected members and showed that the antimicrobial activity of a synthetic DCD peptide resulting from the frameshift mutation was impaired. In order to define the consequences related to a decrease in DCD activity, skin microbiome analyses of different body sites were performed by comparing DCD mutant and wild type samples, and results highlighted significant differences between the groins of mutated and wild type groups. Starting from genetic analysis conducted on an HS family, our findings showed, confirming previous transcriptome results, the potential role of the antimicrobial DCD peptide as an actor playing a crucial part in the etio-pathogenesis of HS and in the maintenance of the skin’s physiological microbiome composition; so, we can hypothesise that DCD could be used as a novel target for personalised therapeutic approach.
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spelling pubmed-97606632022-12-20 A rare loss-of-function genetic mutation suggest a role of dermcidin deficiency in hidradenitis suppurativa pathogenesis Tricarico, Paola Maura Gratton, Rossella dos Santos-Silva, Carlos André de Moura, Ronald Rodrigues Ura, Blendi Sommella, Eduardo Campiglia, Pietro Del Vecchio, Cecilia Moltrasio, Chiara Berti, Irene D’Adamo, Adamo Pio Elsherbini, Ahmed M. A. Staudenmaier, Lena Chersi, Karin Boniotto, Michele Krismer, Bernhard Schittek, Birgit Crovella, Sergio Front Immunol Immunology Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with a multifactorial aetiology that involves a strict interplay between genetic factors, immune dysregulation and lifestyle. Familial forms represent around 40% of total HS cases and show an autosomal dominant mode of inheritance of the disease. In this study, we conducted a whole-exome sequence analysis on an Italian family of 4 members encompassing a vertical transmission of HS. Focusing on rare damaging variants, we identified a rare insertion of one nucleotide (c.225dupA:p.A76Sfs*21) in the DCD gene encoding for the antimicrobial peptide dermcidin (DCD) that was shared by the proband, his affected father and his 11-years old daughter. Since several transcriptome studies have shown a significantly decreased expression of DCD in HS skin, we hypothesised that the identified frameshift insertion was a loss-of-function mutation that might be associated with HS susceptibility in this family. We thus confirmed by mass spectrometry that DCD levels were diminished in the affected members and showed that the antimicrobial activity of a synthetic DCD peptide resulting from the frameshift mutation was impaired. In order to define the consequences related to a decrease in DCD activity, skin microbiome analyses of different body sites were performed by comparing DCD mutant and wild type samples, and results highlighted significant differences between the groins of mutated and wild type groups. Starting from genetic analysis conducted on an HS family, our findings showed, confirming previous transcriptome results, the potential role of the antimicrobial DCD peptide as an actor playing a crucial part in the etio-pathogenesis of HS and in the maintenance of the skin’s physiological microbiome composition; so, we can hypothesise that DCD could be used as a novel target for personalised therapeutic approach. Frontiers Media S.A. 2022-12-05 /pmc/articles/PMC9760663/ /pubmed/36544771 http://dx.doi.org/10.3389/fimmu.2022.1060547 Text en Copyright © 2022 Tricarico, Gratton, Santos-Silva, Moura, Ura, Sommella, Campiglia, Del Vecchio, Moltrasio, Berti, D’Adamo, Elsherbini, Staudenmaier, Chersi, Boniotto, Krismer, Schittek and Crovella https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Tricarico, Paola Maura
Gratton, Rossella
dos Santos-Silva, Carlos André
de Moura, Ronald Rodrigues
Ura, Blendi
Sommella, Eduardo
Campiglia, Pietro
Del Vecchio, Cecilia
Moltrasio, Chiara
Berti, Irene
D’Adamo, Adamo Pio
Elsherbini, Ahmed M. A.
Staudenmaier, Lena
Chersi, Karin
Boniotto, Michele
Krismer, Bernhard
Schittek, Birgit
Crovella, Sergio
A rare loss-of-function genetic mutation suggest a role of dermcidin deficiency in hidradenitis suppurativa pathogenesis
title A rare loss-of-function genetic mutation suggest a role of dermcidin deficiency in hidradenitis suppurativa pathogenesis
title_full A rare loss-of-function genetic mutation suggest a role of dermcidin deficiency in hidradenitis suppurativa pathogenesis
title_fullStr A rare loss-of-function genetic mutation suggest a role of dermcidin deficiency in hidradenitis suppurativa pathogenesis
title_full_unstemmed A rare loss-of-function genetic mutation suggest a role of dermcidin deficiency in hidradenitis suppurativa pathogenesis
title_short A rare loss-of-function genetic mutation suggest a role of dermcidin deficiency in hidradenitis suppurativa pathogenesis
title_sort rare loss-of-function genetic mutation suggest a role of dermcidin deficiency in hidradenitis suppurativa pathogenesis
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9760663/
https://www.ncbi.nlm.nih.gov/pubmed/36544771
http://dx.doi.org/10.3389/fimmu.2022.1060547
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