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Page 364 Garro-Núñez et al. J Transl Genet Genom 2022;6:361-74 https://dx.doi.org/10.20517/jtgg.2022.10

Some benefits associated with mitochondrial uncoupling are the reduction of the proton motive force (Δp),
which causes a local decrease in oxygen concentration and a reduction of reactive oxygen species (ROS)
products [29-31] . Δp plays a very important role in the entry of certain proteins and calcium into the
[29]
mitochondria . In addition, the activation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (mPTP)
involved in the initiation of apoptosis is reduced [29,32] . Additionally, mitochondrial uncoupling promotes
[33]
neuronal survival since these cells are highly oxidative and generate high levels of ROS . Therefore,
PM20D1 may be involved in a method of mitochondrial uncoupling (through NAAs) that modulates ROS
[5]
levels and improves neuronal survival, potentially playing a role in neurodegenerative diseases .
GENE EXPRESSION
Multiple recent studies have shown that PM20D1 expression is, at least in part, genetically determined. Six
SNPs (rs1172198, rs708727, rs823082, rs823088, rs1361754, and rs960603), which are located downstream of
the gene, have been shown to be associated with both PM20D1 methylation and expression levels and are
thus considered methylation QTLs (mQTLs) as well as expression QTLs (eQTLs) [5-8,34] . These SNPs
constitute a haplotype which plays a role in the methylation of the PM20D1 promoter and its expression. As
would be expected, the haplotype associated with higher methylation of the promoter is also associated with
reduced expression of the gene. Sanchez-Mut et al. (2018) proposed that the genomic region where this
haplotype is located acts as a regulatory region and induces repression through interaction with PM20D1’s
promoter via a CTCF-mediated chromatin loop .
[6]
There are other genes on chromosome 1q in partial linkage disequilibrium with PM20D1. A study found a
correlation between the genotype at these SNPs and expression in different tissues for other genes in the
region besides PM20D1, specifically NUCKS1, RAB7L1, and SLC41A1 . Given that an association between
[35]
the genotype at these SNPs (individually or in combination) and different disorders has been
reported [5-8,36,37] , the possibility of genotype-dependent expression for all four genes would raise the question
of which gene is involved in a particular phenotype. To explore this, Sanchez-Mut et al. used a well-
characterized sample of human brains to explore the DNA methylation levels in these four genes and found
a strong correlation between genetic background (SNP genotypes) and CpG methylation only for PM20D1,
as well as a slight correlation for SLC41A1 for only two of the SNPs . Then, they looked at expression levels
[5]
and found a significant correlation between genetic background and expression levels only for the PM20D1
gene, which they also observed in mice. They found a non-significant correlation trend between genotype
and expression for SLC41A1 in the human samples, in the same direction as in PM20D1. Therefore, in the
brain, the genotype at these SNPs seems to strongly influence methylation and expression levels of PM20D1
and possibly a lower degree for SLC41A1, but no effect on NUCKS1 and RAB7L1.

However, SLC41A1 and PM20D1 are differentially regulated by AD-related stressors, with only PM20D1
being upregulated by both amyloid-β and reactive oxygen species and only PM20D1 being neuroprotective
when overexpressed in cell and primary cultures . Therefore, at least in the case of AD, the evidence
[5]
suggests that, from this region, PM20D1 is the main gene whose expression level is related to the phenotype.

From these and other studies, SNP rs708727 has emerged as the most significantly associated with PM20D1
methylation and expression levels in the brain and other tissues. For the other SNPs that constitute a
haplotype with rs708727, the level of association is less significant and varies between studies [5-8,35,38-41] . SNP
rs708727 is a coding variant in the SLC41A1 gene (not PM20D1) that results in the synonymous substitution
p.Asn252Asn (NM_173854). The hypermethylation-associated allele is the A allele, with frequencies that
[42]
vary between 0.3% in East Asians to over 44% in Finnish Europeans, according to gnomAD . In the
presence of the A allele, PM20D1’s promoter is hypermethylated, with the result that there is no