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Page 370 Garro-Núñez et al. J Transl Genet Genom 2022;6:361-74 https://dx.doi.org/10.20517/jtgg.2022.10

[98]
to be differentially methylated .

PM20D1 has a potential role in cancer as well; differentially methylated regions at PM20D1 have been
reported for different types of cancer. As a first example, the methylation level of PM20D1 (together with
other genes) has been proposed to allow detection of the presence of lung cancer, as well as to characterize
the type of tumor . Additionally, hypermethylation at PM20D1 sites has been found in hepatocellular
[99]
carcinoma and acute myeloid leukemia, suggesting that the gene is downregulated or totally silenced [100,101] .

Finally, it is important to highlight the role of PM20D1 in neurological disorders. In addition to its
involvement in AD and PD (as detailed in previous sections), hypermethylation of CpG sites in PM20D1
(and presumably reduced expression) has been associated with an increased risk of suffering chronic
[102]
postsurgical pain . Additionally, it has been reported that PM20D1 is differentially methylated between
[103]
different types of epilepsy (focal vs. generalized epilepsy) .
In most cases, the evidence supporting the role of PM20D1 in these disorders comes from a single report
with a small sample size. Therefore, further studies are needed to confirm these associations, as well as to
understand the mechanisms involved.

CONCLUSION
Evidence supporting the role of the PM20D1 gene in several heterogeneous disorders has been steadily
accumulating in recent years. Thus far, it appears that the main effect of this gene on phenotype comes from
changes in its expression levels, rather than from genetic variants that affect its structure or function.
However, genetic variants in the genomic region close to PM20D1 do play a role in the regulation of the
gene’s expression levels, as has been shown by the multiple studies confirming the existence of these mQTLs
and eQTLs. This stresses the importance of performing comprehensive studies that explore genetic
variation, methylation, and expression at the same time. Although the direction of change in methylation or
expression of PM20D1 varies among disorders, many studies report hypermethylation or reduced
expression of PM20D1 (or a higher frequency of the reduced expression-associated haplotype) in affected
individuals. This (and other functional evidence) supports the idea of the protective role of PM20D1, which
is lost in affected individuals with silenced expression. PM20D1 has been shown to activate mitochondrial
uncoupling, which plays a role in response to oxidative stress. Oxidative stress is known to be involved in
the development and progression of several PM20D1-associated disorders, including obesity, Alzheimer’s
disease, and Parkinson’s disease, and could potentially be the common link among them. The exact
biological mechanisms involved in each case await elucidation, which could potentially open up promising
avenues for treatment.

DECLARATIONS
Acknowledgments
We thank Gabriel Jiménez-Huezo for creating Figures 1 and 2.

Authors’ contributions
Contributed to the conception of the study: Raventós-Vorst H, Chavarría-Soley G
Drafting of the manuscript: Garro-Núñez D, Mora-Cubillo P, Fonseca-Bone S, Picado-Martínez MJ,
Fonseca-Brenes M, Chavarría-Soley G
Supervision: Garro-Núñez D, Raventós-Vorst H, Chavarría-Soley G