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Page 362 Garro-Núñez et al. J Transl Genet Genom 2022;6:361-74 https://dx.doi.org/10.20517/jtgg.2022.10

INTRODUCTION
In the last decades, a large amount of evidence regarding genetic risk variants for most common disorders
[1]
has been generated mostly through genome-wide association studies (GWAS) . However, less attention has
been focused on the changes in methylation and expression associated with different phenotypes. This has
changed in recent years with the increased use of whole-genome methylation and RNA sequencing
[2,3]
techniques (in addition to the long-existing expression microarray analyses). Some of the challenges faced
by studies dealing with methylation and expression include their usually dramatically smaller sample sizes
compared to GWAS, and that they often focus on either rather than both methylation and expression at the
same time.

Such methylation studies have cast a spotlight on an until then little-studied gene, PM20D1, which encodes
an enzyme belonging to the M20 peptidase family . There is growing evidence that differential methylation
[4]
in this gene is associated with several heterogeneous disease phenotypes [Table 1]. Additionally, it was
discovered that genetic variants close to but not inside the gene can influence methylation levels at the
[5-8]
[6]
gene’s promoter , and this methylation correlates with expression . It has been proposed that these
variants had not been previously found in GWAS because the PM20D1 region is not well represented and is
in low linkage disequilibrium with the SNPs included in the common microarrays used in GWAS .
[6]
In this review, we explore the current knowledge regarding the PM20D1 gene. First, we focus on what is
known about its biology, potential functions, and regulation of its expression. We then review the evidence
supporting the involvement of PM20D1 in different phenotypes such as Alzheimer’s disease (AD), obesity,
Parkinson’s disease (PD), and several other disorders.

BIOLOGY
PM20D1 belongs to the mammalian M20 peptidase family . The main function of this secreted enzyme is
[4]
the synthesis and hydrolysis of N-acyl amino acids (NAAs) [9,10] by catalyzing the biosynthesis of NAAs from
free fatty acids and free amino acids, as well as the reverse hydrolysis reaction . This gene is expressed in
[9]
several tissues such as the liver, bladder, brain, large intestine, pancreas, kidney, and heart of mice . In
[11]
humans, it shows a notably high expression in pancreas and skin, but is also expressed in many other
[12]
tissues . In the case of the brain, expression occurs across all brain regions [12,13] and cell types [14,15] . This
peptidase circulates through the bloodstream in tight association with low- and high-density lipoproteins.
These lipoproteins work as coactivators in PM20D1 activity and as biosynthesis sites of the NAAs .
[16]

NAAs are bioactive lipids composed of a fatty acyl chain linked to an amino acid by an amide bond .
[17]
NAAs circulate through the bloodstream, with albumin as a physiologic N-acyl amino acid carrier which
confers resistance to hydrolytic degradation by spatially segregating N-acyl amino acids away from their site
of biosynthesis. Albumin also helps to maintain equilibrium by acting as a buffer between bound inactive
[16]
and free active NAAs . Many NAAs identified in mammals have putative roles associated with different
physiological processes. Some of the biological activities associated with NAAs are vasodilation ,
[18]
neuroprotection , and pain sensation [20,21] . However, many of the biochemical mechanisms that explain the
[19]
role of the NAAs are still unknown .
[22]
Some NAAs have been described as thermogenic, for example, N-acyl-phenylalanines and N-acyl-leucines,
which regulate energy metabolism [9,10,23] . The levels of these NAAs are physiologically increased after cold
exposure and cause an uncoupling of mitochondrial respiration in different peripheral tissues by directly
interacting with mitochondrial proteins [10,24,25] . Mitochondrial uncoupling occurs when ATP is not produced
[26]
through electron transport , but redox energy is released in the form of heat, since protons are lost