Page 39 - Read Online

Page 368 Garro-Núñez et al. J Transl Genet Genom 2022;6:361-74 https://dx.doi.org/10.20517/jtgg.2022.10

Several SNPs in the haplotype associated with PM20D1 expression levels show significant genome-wide
association with BMI [36,51] , while weaker associations with type 2 diabetes and HDL cholesterol levels have
[36]
been reported as well . The direction of these associations is consistent with expectations: variants
associated with lower BMI are also associated with lower diabetes risk and higher HDL cholesterol. For the
SNPs in the haplotype, the strength of association with PM20D1 expression correlates very strongly with the
strength of association with BMI/obesity. However, and again, in contrast to what would be expected from
results in mice studies, the haplotype associated with absent PM20D1 expression is the one associated with
[36]
lower BMI . Consistent with this result, hypomethylation (and presumably increased expression) of
PM20D1 has been reported in a group of women with obesity compared to controls . There is also one
[52]
report of hypermethylation in individuals with obesity .
[47]
The evidence from GWAS suggests that levels of PM20D1 expression (which are at least in part genetically
determined) are associated with BMI and the risk of obesity. However, independent studies have found that
NAA levels do not change significantly in knockout mice for PM20D1 or humans homozygous for the
haplotype associated with silenced PM20D1 expression [10,36] . This suggests that other enzymes generate and
regulate levels of NAAs, and that PM20D1’s effect on the body weight phenotype could involve a
mechanism different from NAA regulation.

PARKINSON’S
The genes PM20D1, SLC41A1, RAB29 (also called RAB7L1), NUCKS1, and SLC5A3 are part of the PARK16
locus . Several investigations have found an association between SNPs of the PARK16 locus and idiopathic
[53]
Parkinson’s disease (PD) [37,53-58] . Nevertheless, results have differed across studies and populations, with
important variations in the SNPs significantly associated with PD and their allelic frequencies in the groups
of cases and controls. The underlying mechanism and the PARK16 genes involved in the onset of PD are
unclear, but putative mechanisms have been suggested for SLC41A1, NUCKS, and RAB29 [59-62] , including
epistasis and allelic heterogeneity models [63,64] .

Despite the lack of known mechanisms involving PM20D1 in the pathogenesis of PD, it is well known that
mitochondrial dysfunction and oxidative stress are present in many PD patients [65,66] . Mitochondrial
dysfunction in PD patients is evidenced by mitochondrial complex I (MCI) deficiency in substantia
nigra [67,68] ; this region contains the dopaminergic neurons that are lost in PD. González-Rodríguez et al.
(2021) recently showed that MCI dysfunction is enough to cause progressive, human-like parkinsonism in
[69]
mice . The partial inhibition of MCI by drugs increases ROS production and promotes cellular oxidative
[72]
stress [70,71] . These processes participate in the damage of the dopaminergic neurons in PD . In addition, the
dopaminergic neurons may be under increased oxidative stress, since the oxidative metabolism of dopamine
produces ROS [73,74] . Given the function of PM20D1 and the role of NAAs as endogenous mitochondrial
uncouplers, as well as their potential role against oxidative activity [5,75,76] , it cannot be ruled out that PM20D1
has a neuroprotective effect on the development of PD.

To the best of our knowledge, only two variants in PM20D1 with significant associations have been
reported. Intronic variant rs11240572 has been significantly [53,77-79] or close to significantly associated with
[80]
the PD phenotype; the minor allele (A) has been proposed to have a protective effect due to its higher
frequency in controls than cases. In contrast, Deng et al. (2019) reported that Chinese PD patients with
rs11240572-A presented a faster progression and greater deterioration of motor function than non-
carriers . The common coding variant rs1891460-C (p.Ile149Val) has been reported as nominally
[81]
[57]
associated with a reduced PD risk in individuals of European and Ashkenazi Jewish ancestry ; there are no
other studies that confirm this association. Few studies have sequenced PM20D1 looking for variants in PD