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Cutaneous and metabolic defects associated with nuclear abnormalities in a transgenic mouse model expressing R527H lamin A mutation causing mandibuloacral dysplasia type A (MADA) syndrome
LMNA gene encodes for lamin A/C, attractive proteins linked to nuclear structure and functions. When mutated, it causes different rare diseases called laminopathies. In particular, an Arginine change in Histidine in position 527 (p.Arg527His) falling in the C-terminal domain of lamin A precursor for...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Pacini Editore Srl
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783430/ https://www.ncbi.nlm.nih.gov/pubmed/33458588 http://dx.doi.org/10.36185/2532-1900-036 |
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author | D’Apice, Maria Rosaria De Dominicis, Angela Murdocca, Michela Amati, Francesca Botta, Annalisa Sangiuolo, Federica Lattanzi, Giovanna Federici, Massimo Novelli, Giuseppe |
author_facet | D’Apice, Maria Rosaria De Dominicis, Angela Murdocca, Michela Amati, Francesca Botta, Annalisa Sangiuolo, Federica Lattanzi, Giovanna Federici, Massimo Novelli, Giuseppe |
author_sort | D’Apice, Maria Rosaria |
collection | PubMed |
description | LMNA gene encodes for lamin A/C, attractive proteins linked to nuclear structure and functions. When mutated, it causes different rare diseases called laminopathies. In particular, an Arginine change in Histidine in position 527 (p.Arg527His) falling in the C-terminal domain of lamin A precursor form (prelamin A) causes mandibuloacral dysplasia Type A (MADA), a segmental progeroid syndrome characterized by skin, bone and metabolic anomalies. The well-characterized cellular models made difficult to assess the tissue-specific functions of 527His prelamin A. Here, we describe the generation and characterization of a MADA transgenic mouse overexpressing 527His LMNA gene, encoding mutated prelamin A. Bodyweight is slightly affected, while no difference in lifespan was observed in transgenic animals. Mild metabolic anomalies and thinning and loss of hairs from the back were the other observed phenotypic MADA manifestations. Histological analysis of tissues relevant for MADA syndrome revealed slight increase in adipose tissue inflammatory cells and a reduction of hypodermis due to a loss of subcutaneous adipose tissue. At cellular levels, transgenic cutaneous fibroblasts displayed nuclear envelope aberrations, presence of prelamin A, proliferation, and senescence rate defects. Gene transcriptional pattern was found differentially modulated between transgenic and wildtype animals, too. In conclusion, the presence of 527His Prelamin A accumulation is further linked to the appearance of mild progeroid features and metabolic disorder without lifespan reduction. |
format | Online Article Text |
id | pubmed-7783430 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Pacini Editore Srl |
record_format | MEDLINE/PubMed |
spelling | pubmed-77834302021-01-14 Cutaneous and metabolic defects associated with nuclear abnormalities in a transgenic mouse model expressing R527H lamin A mutation causing mandibuloacral dysplasia type A (MADA) syndrome D’Apice, Maria Rosaria De Dominicis, Angela Murdocca, Michela Amati, Francesca Botta, Annalisa Sangiuolo, Federica Lattanzi, Giovanna Federici, Massimo Novelli, Giuseppe Acta Myol Original Article LMNA gene encodes for lamin A/C, attractive proteins linked to nuclear structure and functions. When mutated, it causes different rare diseases called laminopathies. In particular, an Arginine change in Histidine in position 527 (p.Arg527His) falling in the C-terminal domain of lamin A precursor form (prelamin A) causes mandibuloacral dysplasia Type A (MADA), a segmental progeroid syndrome characterized by skin, bone and metabolic anomalies. The well-characterized cellular models made difficult to assess the tissue-specific functions of 527His prelamin A. Here, we describe the generation and characterization of a MADA transgenic mouse overexpressing 527His LMNA gene, encoding mutated prelamin A. Bodyweight is slightly affected, while no difference in lifespan was observed in transgenic animals. Mild metabolic anomalies and thinning and loss of hairs from the back were the other observed phenotypic MADA manifestations. Histological analysis of tissues relevant for MADA syndrome revealed slight increase in adipose tissue inflammatory cells and a reduction of hypodermis due to a loss of subcutaneous adipose tissue. At cellular levels, transgenic cutaneous fibroblasts displayed nuclear envelope aberrations, presence of prelamin A, proliferation, and senescence rate defects. Gene transcriptional pattern was found differentially modulated between transgenic and wildtype animals, too. In conclusion, the presence of 527His Prelamin A accumulation is further linked to the appearance of mild progeroid features and metabolic disorder without lifespan reduction. Pacini Editore Srl 2020-12-01 /pmc/articles/PMC7783430/ /pubmed/33458588 http://dx.doi.org/10.36185/2532-1900-036 Text en ©2020 Gaetano Conte Academy - Mediterranean Society of Myology, Naples, Italy https://creativecommons.org/licenses/by-nc-nd/4.0/deed.en This is an open access article distributed in accordance with the CC-BY-NC-ND (Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International) license. The article can be used by giving appropriate credit and mentioning the license, but only for non-commercial purposes and only in the original version. For further information: https://creativecommons.org/licenses/by-nc-nd/4.0/deed.en |
spellingShingle | Original Article D’Apice, Maria Rosaria De Dominicis, Angela Murdocca, Michela Amati, Francesca Botta, Annalisa Sangiuolo, Federica Lattanzi, Giovanna Federici, Massimo Novelli, Giuseppe Cutaneous and metabolic defects associated with nuclear abnormalities in a transgenic mouse model expressing R527H lamin A mutation causing mandibuloacral dysplasia type A (MADA) syndrome |
title | Cutaneous and metabolic defects associated with nuclear abnormalities in a transgenic mouse model expressing R527H lamin A mutation causing mandibuloacral dysplasia type A (MADA) syndrome |
title_full | Cutaneous and metabolic defects associated with nuclear abnormalities in a transgenic mouse model expressing R527H lamin A mutation causing mandibuloacral dysplasia type A (MADA) syndrome |
title_fullStr | Cutaneous and metabolic defects associated with nuclear abnormalities in a transgenic mouse model expressing R527H lamin A mutation causing mandibuloacral dysplasia type A (MADA) syndrome |
title_full_unstemmed | Cutaneous and metabolic defects associated with nuclear abnormalities in a transgenic mouse model expressing R527H lamin A mutation causing mandibuloacral dysplasia type A (MADA) syndrome |
title_short | Cutaneous and metabolic defects associated with nuclear abnormalities in a transgenic mouse model expressing R527H lamin A mutation causing mandibuloacral dysplasia type A (MADA) syndrome |
title_sort | cutaneous and metabolic defects associated with nuclear abnormalities in a transgenic mouse model expressing r527h lamin a mutation causing mandibuloacral dysplasia type a (mada) syndrome |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783430/ https://www.ncbi.nlm.nih.gov/pubmed/33458588 http://dx.doi.org/10.36185/2532-1900-036 |
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