Table 3.
Systematic analysis of the genes currently associated with CP
| Category | Abbreviation | Full name or alias | Function | Mechanistic link with CP |
|---|---|---|---|---|
| Thrombosis-related genes | FVL | The coagulation factor V Leiden mutation | Inhibits the activated protein C activity and prevents inactivation of coagulation factor V. | Thrombophilic genetic factors, particularly FVL and MTHFR, are more frequent in infants with ischemic and hemorrhagic lesions, which are frequently observed in CP. These genetic factors are associated with an increased risk of thrombosis, which can lead to ischemic and hemorrhagic brain lesions, potentially contributing to the development of CP. However, the exact mechanisms are not fully understood and more research is needed to confirm these findings. |
| Leading to the overproduction of thrombin, excessive blood clotting, and increased risk of thrombosis. | ||||
| MTHFR | 5,10-methylenetetrahydrofolate reductase | Associated with the maintenance of low levels of homocysteine. | ||
| Gene mutation results in unregulated homocysteine levels. | ||||
| Elevated homocysteine levels can damage vascular endothelial cells | ||||
| NOS | Nitric oxide synthase | Neuronal NOS which participates in cellular communication within the nervous tissue; inducible NOS which assists macrophages to participate in immune actions; endothelial NOS which participates in the vascular function regulation. | ||
| Mitochondrion- and oxidative phosphorylation metabolism disorder-related genes | MFF | Mitochondrial fission factor | A nuclear gene that encodes a protein involved in mitochondrial and peroxisomal fission. | The relationship between mitochondrial- and oxidative phosphorylation metabolism disorder-related genes and CP is intricate. Studies have shown that mitochondrial dysfunction and oxidative stress can lead to neuronal damage, a key feature of CP. In particular, the genes involved in mitochondrial and oxidative phosphorylation metabolism are often found to be dysregulated in CP patients. This dysregulation can lead to energy metabolism disorders, which can further exacerbate neuronal damage and contribute to the symptoms of CP. |
| ACADM | Acyl-CoA dehydrogenase medium chain | Mitochondrial fatty acid beta-oxidation and PPAR-α activates gene expression. | ||
| FAR1 | Fatty acyl-CoA reductase 1 | FAR1-related disorders include peroxisomal fatty acyl coenzyme triglyceride reductase 1 disorder, cataracts, spastic paraparesis, and bradylalia. | ||
| APOE | apolipoprotein E | Controls the synthesis of apolipoprotein E | ||
| PDHX | Pyruvate dehydrogenase complex component X | Pyruvate metabolism and ESR-mediated signaling. | ||
| GCDH | Glutaryl-CoA dehydrogenase | Super pathway of tryptophan utilization and metabolism | ||
| Angiogenesis-related genes | COL4A1/COL4A2 | Encode IV collagen | The COL4A1 gene encodes type IV alpha collagen. The C-terminal portion of the COL4A2 protein, called cantharidin, is an angiogenesis and tumor growth inhibitor. |
The relationship between angiogenesis-related genes (COL4A1/COL4A2) and CP is quite significant. Mutations in the collagen genes COL4A1 and COL4A2 can lead to arterial basement membrane thickening, resulting in a multisystem microangiopathy that targets the central nervous system and potentially affects other systems such as the ocular, renal, cardiac, and muscular systems. Within the brain, these changes predispose individuals to recurrent ischemic and/or hemorrhagic strokes, which can begin during early fetal development and extend into the postnatal period and even into adulthood. These stroke-related complications may be insidious and clinically silent. Neuroimaging phenotypes of COL4A-associated disease include chronic white matter disease, porencephaly/ hydranencephaly, encephalomalacia, cerebral calcifications, schizencephaly, and hydrocephalus. The corresponding clinical diagnoses include CP intellectual disability, cortical visual impairment, and epilepsy. Therefore, mutations in the COL4A1 and COL4A2 genes significantly contribute to the development of CP and other neurological conditions. |
| Neuronal migration disorder-related genes | TYW1 | TRNA-YW synthesizing protein 1 homolog | TRNA-YW synthesizing protein 1 homolog (TYW1) is a tRNA super-modifying enzyme; The recombinant glycerol-3-phosphate acyltransferase, mitochondrial (GPAM) is a mitochondrial enzyme. | Neuronal migration, a critical process in brain development, has been linked to CP. Disruptions in neuronal migration can cause issues in motion and cognition by hindering neuronal proliferation and migration, as observed in some CP patients. Moreover, evidence suggests that there may be attempts at neuronal repair or regeneration in neonatal white matter injury, a characteristic of CP. |
| ZDHHC15 | Zinc finger DHHC-type palmitoyltransferase 15 | ZDHHC15-related disorders include spastic diplegia and non-syndromic X-linked mental retardation 91 (MRX91). | ||
| TNR | The tenascin R | Encodes a member of the tenascin family of extracellular matrix glycoproteins. | ||
| CTNNB1 | Catenin Beta 1 | Part of a complex of proteins that constitute adherens junctions. | ||
| Calcium ion correlation | ITPR1 | Inositol 1,4,5-Trisphosphate Receptor Type 1 | Release of calcium ions from endoplasmic reticulum. | Calcium ions play a significant role in various neurological functions, including neural cell-cell interactions, synaptic transmission, and axon guidance. Disruptions in these functions, such as those caused by genetic alterations affecting calcium ion channels, can contribute to the development of CP. |
| CACNA1A/D | Calcium voltage-gated channel subunit alpha 1 A/D. | Voltage-dependent calcium channels | ||
| PCDH12 | Protocadherin 12 | A subfamily of the cadherin superfamily. | ||
| GTP/ATP | ATL1 | Atlastin GTPase 1 | GTPase and a Golgi body transmembrane protein. | GTP and ATP are essential energy sources for various biological processes. In the context of CP, a condition characterized by motor impairment, the role of ATP is particularly significant. ATP is primarily produced by mitochondrial organelles within muscle fibers, powering the force generation needed for movement. In children with CP, there is a marked reduction in mitochondrial function, which can lead to decreased ATP production. This reduction in ATP can contribute to the increased energetics of movement, reduced endurance capacity, and increased perceived effort observed in CP patients. Therefore, the correlation between GTP/ATP and CP is largely tied to energy production and muscle function |
| GCH1 | GTP cyclohydrolase 1 | A member of the GTP cyclohydrolase family, and the first and rate-limiting enzyme in tetrahydrobiopterin (BH4) biosynthesis | ||
| GNAO1 | G protein subunit alpha O1 | The alpha subunit of the Go heterotrimeric G-protein signal-transducing complex. | ||
| SPATA5L1 | Spermatogenesis associated 5 Like 1 | Enable ATP binding activity. Located in cytoplasm and spindle. | ||
| Gene transcription related factor | AUTS2 | Autism susceptibility gene 2 protein | Gene expression (transcription) and assembly of the pre-replicative complex. | The processes of pre-mRNA, tRNA processing, and cell cycle regulation are fundamental to cellular function and development. Disruptions in these processes can lead to various disorders, including CP. For instance, tRNA-derived fragments (tRFs), generated by the specific cleavage of pre- and mature tRNAs, have been found to play crucial roles in cellular processes such as inhibiting protein translation, modulating stress response, regulating gene expression, and involvement in cell cycles. Dysregulation of these tRFs has been associated with various diseases. While direct links between these processes and CP are not explicitly stated in the literature, it is plausible that abnormalities in these fundamental cellular processes could contribute to the neuronal dysfunction observed in CP |
| TRMT5 | TRNA methyltransferase 5 | tRNA Processing and processing of capped intron-containing pre-mRNA. | ||
| NSRP1 | Nuclear speckle splicing regulatory protein 1 | Processing of capped intron-containing pre-mRNA. | ||
| SOX10 | SRY-box transcription factor 10 | Nervous system development and ERK signaling. | ||
| DDX3X | DEAD-Box helicase 3 X-linked | Innate immune system and Toll-like receptor signaling pathway. | ||
| RNASEH2B | Ribonuclease H2 subunit B | Pathways of nucleic acid metabolism and innate immune sensing. | ||
| ATM | Ataxia telangiectasia mutated | Cell cycle regulation related to ataxia-telangiectasia and mantle cell lymphoma | ||
| Other proteins | ARG1 | Arginase 1 | Super pathway of L-citrulline metabolism and innate immune system. | |
| UBE3A | Ubiquitin protein ligase E3A | Class I MHC-mediated antigen processing and presentation and MIF-mediated glucocorticoid regulation. | ||
| ZC4H2 | Zinc finger C4H2-type containing | Plays a role in interneurons differentiation. Involved in neuronal development and in neuromuscular junction formation. | ||
| HPRT1 | Hypoxanthine phosphoribosyltransferase 1 | Nucleotide salvage and thiopurine pathway, Pharmacokinetics/pharmacodynamics. | ||
| FAR1 | Fatty Acyl-CoA Reductase 1 | Metabolism and wax and plasmalogen biosynthesis. | ||
| PDHA1 | Pyruvate dehydrogenase E1 subunit alpha 1 | Pyruvate metabolism and glycolysis (BioCyc). | ||
| KCNQ2 | Potassium voltage-Gated channel subfamily Q member 2 | A slowly activating and deactivating potassium channel | ||
| TUBB4A | Tubulin beta 4A class IVa | A member of the beta tubulin family |
ATP: Adenosine triphosphate; CP: cerebral palsy; GTP: guanosine triphosphate.