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Aging-US: Aging phenotype of MDPL syndrome associated with impaired DNA repair capacity

'These results suggest an alteration in DNA replication/repair function of POLD1 as a primary pathogenetic cause of MDPL.'

Peer-Reviewed Publication

Impact Journals LLC

Figure 6

image: DNA repair kinetics after 1 Gy of X-irradiation. (A) DNA repair kinetics evidenced by γH2AX foci in serum-fed and serum-depleted cells after 1 Gy of X-irradiation. (B) Telomere-induced foci (TIF) in unirradiated fibroblasts at different population doubling levels (PDL). (C) Time course of TIF in serum-fed and serum-depleted cells after 1 Gy of X-irradiation. (D) Representative image of Telomeres stained with anti-TRF1 antibody (green), foci stained with anti-γH2AX antibody (red), and DAPI-stained nucleus (blue). Magnification 200X; inset shows co-localization of both antibodies, indicating a TIF. (E) Ratio between telomeric and centromeric fluorescence: T/C. (F) Representative image of chromosome spread showing telomere doublet (arrowhead) and telomere loss (arrow). Magnification 63X. (G) Telomere loss (circles, dashed lines) and telomere doublets (squares, continuous lines) at different PDL. WT in grey, MDPL in black. view more 

Credit: Correspondence to: Maria Rosaria D'Apice email: and Antonella Sgura email:

Aging-US published "Functional analysis of POLD1 p.ser605del variant: the aging phenotype of MDPL syndrome is associated with an impaired DNA repair capacity" which reported that 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.

A decline of cell growth, cellular senescence and a blockage of proliferation in G0/G1 phase complete the aged cellular picture.

Moreover, the rate of telomere shortening was greater in pathological cells, suggesting the telomere dysfunction as an emerging key feature in MDPL.

These 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.

Dr. Maria Rosaria D'Apice The Tor Vergata Hospital and Dr. Antonella Sgura from "Roma Tre" University said, "Mandibular hypoplasia, Deafness and Progeroid features with concomitant Lipodystrophy, represent a rare systemic disorder, named MDPL syndrome (MDPL; OMIM #615381)"

MDPL was described for the first time in 2010, reporting seven subjects showing a clinical phenotype overlapping with mandibuloacral dysplasia syndromes such as mandibular hypoplasia, prominent eyes, stiff joints, beaked nose, and lipodystrophy, but also specific additional clinical hallmarks, including sensorineural hearing loss, hypogonadism and absent clavicular hypoplasia/acroosteolyses.

MAD and MDPL belong to the group of diseases characterized by premature aging, which can be caused by inheritable nuclear envelope and/or DNA repair defects.

Song and colleagues also demonstrated that POLD1 downregulation is able to block the cell cycle at G1 and G2/M phases and results in reduced DNA synthesis, demonstrating the potential role of POLD1 in the regulation of cell cycle progression.

Polδ serves to repair DNA lesions arising as a result of exposure to mutagens, acting in multiple forms of DNA repair, including nucleotide excision repair, double strand break repair, base excision repair, and mismatch repair.

In particular, these researchers shed light on the capacity of MDPL cells to respond and repair DNA induced-damage, especially at telomeric level.

The understanding of the pathogenic mechanism lying at the basis of the MDPL syndrome allows us to explore the link existing among DNA repair and age-related diseases.

The D'Apice/Sgura Research Team concluded in their Aging-US Research Output, "In order to respond to some of these intriguing questions, we are now generating human induced pluripotent stem cells from patient's fibroblasts for applying genome-editing technologies, like the CRISPR-Cas9 nucleases, as tool for drug screening applications targeting DNA repair and development of therapeutic treatment."


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Correspondence to: Maria Rosaria D'Apice email: and Antonella Sgura email:

Keywords: MDPL syndrome, POLD1 gene, age-related disease, DNA repair, telomere damage

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research as well as topics beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, cancer, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR among others), and approaches to modulating these signaling pathways.

To learn more about Aging-US, please visit or connect with @AgingJrnl

Aging-US is published by Impact Journals, LLC please visit or connect with @ImpactJrnls

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