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Functional analysis of POLD1 p.ser605del variant: the aging phenotype of MDPL syndrome is associated with an impaired DNA repair capacity

Mandibular hypoplasia, Deafness and Progeroid features with concomitant Lipodystrophy define a rare systemic disorder, named MDPL Syndrome, due to almost always a de novo variant in POLD1 gene, encoding the DNA polymerase δ. We report a MDPL female heterozygote for the recurrent p.Ser605del variant....

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Autores principales: Murdocca, Michela, Spitalieri, Paola, De Masi, Claudia, Udroiu, Ion, Marinaccio, Jessica, Sanchez, Massimo, Talarico, Rosa Valentina, Fiorillo, Chiara, D’Adamo, Monica, Sbraccia, Paolo, D’Apice, Maria Rosaria, Novelli, Giuseppe, Sgura, Antonella, Sangiuolo, Federica
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7950258/
https://www.ncbi.nlm.nih.gov/pubmed/33618333
http://dx.doi.org/10.18632/aging.202680
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author Murdocca, Michela
Spitalieri, Paola
De Masi, Claudia
Udroiu, Ion
Marinaccio, Jessica
Sanchez, Massimo
Talarico, Rosa Valentina
Fiorillo, Chiara
D’Adamo, Monica
Sbraccia, Paolo
D’Apice, Maria Rosaria
Novelli, Giuseppe
Sgura, Antonella
Sangiuolo, Federica
author_facet Murdocca, Michela
Spitalieri, Paola
De Masi, Claudia
Udroiu, Ion
Marinaccio, Jessica
Sanchez, Massimo
Talarico, Rosa Valentina
Fiorillo, Chiara
D’Adamo, Monica
Sbraccia, Paolo
D’Apice, Maria Rosaria
Novelli, Giuseppe
Sgura, Antonella
Sangiuolo, Federica
author_sort Murdocca, Michela
collection PubMed
description Mandibular hypoplasia, Deafness and Progeroid features with concomitant Lipodystrophy define a rare systemic disorder, named MDPL Syndrome, due to almost always a de novo variant in POLD1 gene, encoding the DNA polymerase δ. We report a MDPL female heterozygote for the recurrent p.Ser605del variant. In order to deepen the functional role of the in frame deletion affecting the polymerase catalytic site of the protein, cellular phenotype has been characterised. MDPL fibroblasts exhibit in vitro nuclear envelope anomalies, accumulation of prelamin A and presence of micronuclei. A decline of cell growth, cellular senescence and a blockage of proliferation in G0/G1 phase complete the aged cellular picture. The evaluation of the genomic instability reveals a delayed recovery from DNA induced-damage. Moreover, the rate of telomere shortening was greater in pathological cells, suggesting the telomere dysfunction as an emerging key feature in MDPL. Our results suggest an alteration in DNA replication/repair function of POLD1 as a primary pathogenetic cause of MDPL. The understanding of the mechanisms linking these cellular characteristics to the accelerated aging and to the wide spectrum of affected tissues and clinical symptoms in the MDPL patients may provide opportunities to develop therapeutic treatments for progeroid syndromes.
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spelling pubmed-79502582021-03-23 Functional analysis of POLD1 p.ser605del variant: the aging phenotype of MDPL syndrome is associated with an impaired DNA repair capacity Murdocca, Michela Spitalieri, Paola De Masi, Claudia Udroiu, Ion Marinaccio, Jessica Sanchez, Massimo Talarico, Rosa Valentina Fiorillo, Chiara D’Adamo, Monica Sbraccia, Paolo D’Apice, Maria Rosaria Novelli, Giuseppe Sgura, Antonella Sangiuolo, Federica Aging (Albany NY) Research Paper Mandibular hypoplasia, Deafness and Progeroid features with concomitant Lipodystrophy define a rare systemic disorder, named MDPL Syndrome, due to almost always a de novo variant in POLD1 gene, encoding the DNA polymerase δ. We report a MDPL female heterozygote for the recurrent p.Ser605del variant. In order to deepen the functional role of the in frame deletion affecting the polymerase catalytic site of the protein, cellular phenotype has been characterised. MDPL fibroblasts exhibit in vitro nuclear envelope anomalies, accumulation of prelamin A and presence of micronuclei. A decline of cell growth, cellular senescence and a blockage of proliferation in G0/G1 phase complete the aged cellular picture. The evaluation of the genomic instability reveals a delayed recovery from DNA induced-damage. Moreover, the rate of telomere shortening was greater in pathological cells, suggesting the telomere dysfunction as an emerging key feature in MDPL. Our results suggest an alteration in DNA replication/repair function of POLD1 as a primary pathogenetic cause of MDPL. The understanding of the mechanisms linking these cellular characteristics to the accelerated aging and to the wide spectrum of affected tissues and clinical symptoms in the MDPL patients may provide opportunities to develop therapeutic treatments for progeroid syndromes. Impact Journals 2021-02-22 /pmc/articles/PMC7950258/ /pubmed/33618333 http://dx.doi.org/10.18632/aging.202680 Text en Copyright: © 2021 Murdocca et al. https://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Murdocca, Michela
Spitalieri, Paola
De Masi, Claudia
Udroiu, Ion
Marinaccio, Jessica
Sanchez, Massimo
Talarico, Rosa Valentina
Fiorillo, Chiara
D’Adamo, Monica
Sbraccia, Paolo
D’Apice, Maria Rosaria
Novelli, Giuseppe
Sgura, Antonella
Sangiuolo, Federica
Functional analysis of POLD1 p.ser605del variant: the aging phenotype of MDPL syndrome is associated with an impaired DNA repair capacity
title Functional analysis of POLD1 p.ser605del variant: the aging phenotype of MDPL syndrome is associated with an impaired DNA repair capacity
title_full Functional analysis of POLD1 p.ser605del variant: the aging phenotype of MDPL syndrome is associated with an impaired DNA repair capacity
title_fullStr Functional analysis of POLD1 p.ser605del variant: the aging phenotype of MDPL syndrome is associated with an impaired DNA repair capacity
title_full_unstemmed Functional analysis of POLD1 p.ser605del variant: the aging phenotype of MDPL syndrome is associated with an impaired DNA repair capacity
title_short Functional analysis of POLD1 p.ser605del variant: the aging phenotype of MDPL syndrome is associated with an impaired DNA repair capacity
title_sort functional analysis of pold1 p.ser605del variant: the aging phenotype of mdpl syndrome is associated with an impaired dna repair capacity
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7950258/
https://www.ncbi.nlm.nih.gov/pubmed/33618333
http://dx.doi.org/10.18632/aging.202680
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