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Human Genetic Diseases Linked to the Absence of NEMO: An Obligatory Somatic Mosaic Disorder in Male

De novo somatic mutations are well documented in diseases such as neoplasia but are rarely reported in rare diseases. Hovewer, severe genetic diseases that are not compatible with embryonic development are caused exclusively by deleterious mutations that could only be found as mosaic and not as inhe...

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Autores principales: Pescatore, Alessandra, Spinosa, Ezia, Casale, Carmela, Lioi, Maria Brigida, Ursini, Matilde Valeria, Fusco, Francesca
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8835834/
https://www.ncbi.nlm.nih.gov/pubmed/35163099
http://dx.doi.org/10.3390/ijms23031179
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author Pescatore, Alessandra
Spinosa, Ezia
Casale, Carmela
Lioi, Maria Brigida
Ursini, Matilde Valeria
Fusco, Francesca
author_facet Pescatore, Alessandra
Spinosa, Ezia
Casale, Carmela
Lioi, Maria Brigida
Ursini, Matilde Valeria
Fusco, Francesca
author_sort Pescatore, Alessandra
collection PubMed
description De novo somatic mutations are well documented in diseases such as neoplasia but are rarely reported in rare diseases. Hovewer, severe genetic diseases that are not compatible with embryonic development are caused exclusively by deleterious mutations that could only be found as mosaic and not as inherited mutations. We will review here the paradigmatic case of Incontinentia Pigmenti, a rare X-linked dominant disease caused by deficiency of the NEMO (also called IKKgamma) protein, which plays a pivotal role in tissue homeostasis. The loss-of-function mutations of NEMO are embryonically lethal in males while females survive because of unbalanced X-inactivation due to NEMO wild type (WT) expressing cells survival despite of NEMO mutant expressing cells. The few surviving IP males are obligatory mosaic mutants with the typical clinical presentation of IP in female. Indeed, the IP pathogenesis in the female and most likely also in the male somatic mosaics is based on the cellular effects of an impaired NEMO activity, but in the context of the interaction of genetically different cells in the affected tissue, which might underline the inflammatory status.
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spelling pubmed-88358342022-02-12 Human Genetic Diseases Linked to the Absence of NEMO: An Obligatory Somatic Mosaic Disorder in Male Pescatore, Alessandra Spinosa, Ezia Casale, Carmela Lioi, Maria Brigida Ursini, Matilde Valeria Fusco, Francesca Int J Mol Sci Review De novo somatic mutations are well documented in diseases such as neoplasia but are rarely reported in rare diseases. Hovewer, severe genetic diseases that are not compatible with embryonic development are caused exclusively by deleterious mutations that could only be found as mosaic and not as inherited mutations. We will review here the paradigmatic case of Incontinentia Pigmenti, a rare X-linked dominant disease caused by deficiency of the NEMO (also called IKKgamma) protein, which plays a pivotal role in tissue homeostasis. The loss-of-function mutations of NEMO are embryonically lethal in males while females survive because of unbalanced X-inactivation due to NEMO wild type (WT) expressing cells survival despite of NEMO mutant expressing cells. The few surviving IP males are obligatory mosaic mutants with the typical clinical presentation of IP in female. Indeed, the IP pathogenesis in the female and most likely also in the male somatic mosaics is based on the cellular effects of an impaired NEMO activity, but in the context of the interaction of genetically different cells in the affected tissue, which might underline the inflammatory status. MDPI 2022-01-21 /pmc/articles/PMC8835834/ /pubmed/35163099 http://dx.doi.org/10.3390/ijms23031179 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Pescatore, Alessandra
Spinosa, Ezia
Casale, Carmela
Lioi, Maria Brigida
Ursini, Matilde Valeria
Fusco, Francesca
Human Genetic Diseases Linked to the Absence of NEMO: An Obligatory Somatic Mosaic Disorder in Male
title Human Genetic Diseases Linked to the Absence of NEMO: An Obligatory Somatic Mosaic Disorder in Male
title_full Human Genetic Diseases Linked to the Absence of NEMO: An Obligatory Somatic Mosaic Disorder in Male
title_fullStr Human Genetic Diseases Linked to the Absence of NEMO: An Obligatory Somatic Mosaic Disorder in Male
title_full_unstemmed Human Genetic Diseases Linked to the Absence of NEMO: An Obligatory Somatic Mosaic Disorder in Male
title_short Human Genetic Diseases Linked to the Absence of NEMO: An Obligatory Somatic Mosaic Disorder in Male
title_sort human genetic diseases linked to the absence of nemo: an obligatory somatic mosaic disorder in male
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8835834/
https://www.ncbi.nlm.nih.gov/pubmed/35163099
http://dx.doi.org/10.3390/ijms23031179
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