Open AccessFunctional analysis of POLD1 p.ser605del variant: the aging phenotype of MDPL syndrome is associated with an impaired DNA repair capacity
Author(s) -
Michela Murdocca,
Paola Spitalieri,
Claudia De Masi,
Ion Udroiu,
Jessica Marinaccio,
Massimo Sanchez,
Rosa Valentina Talarico,
Chiara Fiorillo,
Monica D’Adamo,
Paolo Sbraccia,
Maria Rosaria D’Apice,
Giuseppe Novelli,
Antonella Sgura,
Federica Sangiuolo
Publication year - 2021
Publication title -
aging
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.473
H-Index - 90
ISSN - 1945-4589
DOI - 10.18632/aging.202680
Subject(s) - phenotype , dna repair , genetics , clinical phenotype , biology , dna damage , dna , gene
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.