There are several genes mapped on chromosomes 13 and 18 recognized as the players in the maintenance of redox balance
[58]. Chromosome 13 mapping demonstrated the presence of genes associated with copper transport (ATPase copper transporting beta;
ATP7B), tumor suppression (breast cancer 2;
BRCA2), the inhibition of cell cycle processes, chromatin remodeling (retinoblastoma transcriptional corepressor 1;
RB1), chromosome stability maintenance and regulations of chromosome segregation in mitosis (chromosome alignment-maintaining phosphoprotein 1;
CHAMP1), and oxidative mitochondrial processes (mitochondrial intermediate peptidase;
MIPEP), all of which are relevant in T13 pathogenesis
[59][60][61][62]. The proper expression of the
ATP7B gene is implicated in copper homeostasis, the deregulation of which may result in the development of many pathologies, especially those related to metabolic, cardiovascular and neurodegenerative diseases, and cancer
[63]. Interestingly, the proper expression of
ATP7B is crucial for mitochondrial protection against increased oxidative stress conditions, being an essential micronutrient for proper SOD-1 and mitochondrial complex IV activities
[64]. In this case, this gene triplication may lead to an increased possibility of mtDNA mutation, resulting in subsequent oxidative stress disturbances according to the lack of mitochondrial antioxidant defense
[65]. The
BRCA2 gene is also responsible for oxidative stress homeostasis; its overexpression correlates with increases in oxidative stress-restricted mtDNA replication, resulting in a disturbed mitochondrial oxidative balance
[66]. Moreover, alterations in
MIPEP expression, involved in oxidative phosphorylation (OXPHOS)-related protein maturation, may additionally indicate a connection between mitochondrial dysfunction and T13 development
[62][67]. Moreover, the study performed by Renaudin et al. showed that
BRCA2 deficiency impairs ribonuclease H1 (RNaseH1) function, which is required to ensure mtDNA maintenance
[66]. Interestingly, other genes, such as
RB1 and
CHAMP1, are also related to oxidative-stress-related processes. It has been suggested that disturbances in
RB1 gene expression are involved in DNA damage sensor activity, forkhead box O (Foxo) transcription factors, and p38 mitogen-activated protein kinase processes, for which a disturbed expression affects cell-cycle progression, antioxidant capacity, mitochondrial mass, and cellular metabolism
[68][69][70][71][72].
CHAMP1 encodes a protein with a function in kinetochore–microtubule attachment and in the regulation of chromosome segregation. These properties are performed by their interaction and regulation of cell structure organization preceding mitosis, both of which are known to be important for proper fetal development
[73][74]. Moreover, proper
MIPEP expression is essential to maintain the normal level of mitochondrial sirtuin 3, which is considered a key regulator of oxidative stress by the deacetylation of the substrates involved in both ROS production and detoxification
[75][76][77]. These mechanisms link oxidative stress to mitochondrial dysfunction and may be induced by the triplication of genes implicated in mitochondrial protective processes
[78]. Referring to the fact that mitochondrial dysfunction is assumed to be one of the main T21-related symptoms
[28][79], similar dysfunctions seem to be implicated in T13 development
[59][66].
Furthermore, several important genes involved in intracellular cholesterol trafficking (Niemann–Pick C1 protein;
NPC1 gene), proper DNA transcription and signal transduction (mothers against decapentaplegic homolog;
SMAD), and mitochondrial membrane function (ferrochelatase enzyme, coded by ferrochelatase;
FECH gene) are mapped on chromosome 18
[80][81][82]. The
NPC1 gene encodes a crucial protein and affects the excitability of endosome and lysosome membranes, with characteristic mediation properties in intracellular cholesterol trafficking through cholesterol binding
[80][83][84]. Interestingly,
NPC1 deficiency is related to neurodegenerative disease development due to oxidative damage. In this case, the
NPC1 gene’s correct expression is essential for oxidative stress balance
[85]. Moreover, SMAD proteins are signal transducers and transcriptional modulators involved in multiple signaling pathways, such as cell growth, apoptosis, morphogenesis, and immune responses
[81][86][87]. Research conducted by Xui et al. showed that
SMAD overexpression results in increased oxidative stress and a reduction in cell viability with subsequent induction of apoptosis
[88]. The
FECH gene, which encodes the ferrochelatase enzyme, essential for the proper catalyzation of the insertion of the ferrous form of iron into the protoporphyrin heme synthesis pathway, is also related to oxidative stress homeostasis
[82][89][90][91] (
Table 2).