Research Paper Volume 13, Issue 4 pp 4926—4945
Functional analysis of POLD1 p.ser605del variant: the aging phenotype of MDPL syndrome is associated with an impaired DNA repair capacity
- 1 Department of Biomedicine and Prevention, Tor Vergata University, Rome 00133, Italy
- 2 Department of Science, “Roma Tre” University, Rome 00154, Italy
- 3 Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome 00161, Italy
- 4 Paediatric Neurology and Neuromuscular Disorders, University of Genoa and Istituto Gaslini, Genoa 16147, Italy
- 5 Department of Systems Medicine, Tor Vergata University, Rome 00133, Italy
- 6 Laboratory of Medical Genetics, Tor Vergata Hospital, Rome 00133, Italy
Received: October 29, 2020 Accepted: January 4, 2021 Published: February 22, 2021https://doi.org/10.18632/aging.202680
How to Cite
Copyright: © 2021 Murdocca et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.