Table 2.
Non-syndromic genes: interaction effects of genes and environmental risk factors on oral clefts
| Gene | Functional Role | Risk Factor | Reference |
|---|---|---|---|
| Cytochrome P450 Proteins (CYP) CYPIA1, CYPIA2, CYPIB1 CYP2E1 | Highly polymorphic, having multiple functional alleles; Role in detoxification; metabolism of endogenous morphogens in the developing foetus. | Negative gene-smoking interaction effect | 155-157 |
| Epoxide Hydrolase (EPHX) | Class of proteins that catalyze the hydration of chemically reactive epoxides into their corresponding dihydrodiol products. | ||
| EPHX | Plays an important role in both the bioactivation and detoxification of exogenous chemicals such as PAHs, which are present in cigarette smoke. | Negative gene-smoking interaction effect | 155, 158 |
| EPHX1 Y113H | Variant of EPHX 1 found in the foetus and maternal smoking. | Positive gene-smoking interaction effect | 28, 159 |
| Glutathione Transferase Gene Family (GST) | Families of dimeric phase II enzymes that catalyze the conjugation of reduced glutathione with electrophilic groups of a wide variety of environmental agents. | ||
| GSTM1 | Major gene detoxifying PAHs and widely studied in many disorders and cancers. | Negative gene-smoking interaction effect | 160, 161 |
| GSTT1 | Expressed in a variety of tissues/organs such as erythrocytes, lung, kidney, brain, skeletal muscles, heart, and small intestine; elevated expression profile at the craniofacial regions during embryonic development. | Positive gene-smoking interaction effect | 162, 28, 157, 159 |
| GSTP1 | Major gene detoxifying PAHS; involvement in variety of disorders and cancers. Major enzyme involved in the inactivation of cigarette smoker's metabolites; most important isoform at the embryonic and early foetal developmental stages. | Positive gene-smoking interaction effect | 163, 28, 159 |
| GST A4 / GSTM3 | Two other types of GST gene family members. | Positive gene-smoking interaction effect | 28, 159 |
| Hypoxia-Induced Factor-1 (HIF1A) | Mechanism by which maternal smoking may affect embryonic development due to the production of carbon monoxide, which interferes with oxygen transfer to the placenta, or nicotine, which constricts the uterine wall resulting in hypoxia. | Positive gene-smoking interaction effect | 28, 159 |
| Arylamine N-Acetyltransferase gene Family | N-conjugation of arylamine by the action of N-acetyltransferases (NATs), UDP glucoronosyltransferases (UGTs), or sulfotransferases (SULTS) produces nontoxic compounds. | ||
| N-acetyltransferases1 (NAT 1) | Expressed in many tissues such as erythrocytes, bladder, lymphocytes, neural tissues, liver and intestines. | Negative gene-smoking interaction effect | 19, 164, 165 |
| N-acetyltransferases pseudogene, (NATP1) | Pseudogene identified, which is located at chromosome 8p23.1-8p21.3. | 19, 164, 165 | |
| N-acetyltransferases2 (NAT 2) | Expressed in the liver and epithelial cells of the intestine. | Positive gene-smoking interaction effect | 28, 157, 159 |
| Methylenetetrahydrofolate reductase (MTHFR) | Metabolism of folate by reducing methylenetrahydrofolate, primary donor for methionine synthesis. | Positive gene-smoking interaction effect | 166-172 |
| MTHFRC677T | Variant of methylenetetrahydrofolate reductase. | Negative gene-smoking interaction effect | |
| OTHER METABOLIC GENES | |||
| NAD(P)H quinine oxidoreductase (NQO1) | Flavoenzyme that catalyzes two electron reduction of quinine compounds to hydroquinone and is inducible by oxidative stress, dioxin, and PAHS found in cigarette smoke | Negative gene-smoking interaction effect | 28, 159 |
| SULT1A1 | Catalyzes transfer of the sulfonate group from the active sulfate to a substrate to form the respective sulfate or sulfamate ester. | Negative gene-smoking interaction effect | 28, 159 |
| UDP glycosyltransferases (UGTs) UGT1A7 variant | Catalyzes conjugation reactions where hydrophobic chemicals are transformed into water-soluble compounds. Potential maternal effects on embryonic development. | Positive gene-smoking interaction effect | 159, 173, 174 |
| DEVELOPMENTAL GENES FOR ORAL CLEFTS | |||
| Transforming Growth Factor A (TGF α) | Transmembrane protein expressed at the medial edge of the epithelium (MEE) of fusing palatal shelves. Its receptor epidermal growth factor (EGFR) is expressed in the degenerating MEE. | Positive gene-smoking interaction effect (smoking, alcohol drinking, vitamins) | 175-177 |
| Transforming growth Factor β-3 (TGF β3) | Regulator of many biological processes such as proliferation, differentiation, epithelial mesenchymal transformation and apoptosis. | Positive gene-smoking interaction effect (smoking, alcohol drinking) | 81, 176, 178 |
| Muscle Segment Homeobox1 (MSX1) | Transcriptional repressor important in craniofacial, limb, and nervous system development. | Positive gene-smoking interaction effect (smoking and alcohol drinking) | 176, 179, 180 |
| MSX2 | Similar to MSX1; rare cause of isolated cleft lip with or without cleft palate. | 179, 180 | |
| Acyl-CoA desaturase ACOD4 | Pericentric inversion disrupts a gene (ACOD4) on chromosome 4q21 that codes for a novel acyl-CoA desaturase enzyme that occurs in a single two-generation family with CL. | 181 | |
| Retinoic acid receptor (RAR) | Odds ratios for transmission of alleles at THRA1 were significant when ethnic group was included. | Negative gene-smoking interaction effect | 176 |
| CHD7 | Chromodomain helicase DNA-binding proteins. | 182 | |
| ESR1 | Ligand-activated TF estrogen receptor. | 183 | |
| FGF/ FGFR families FGF8 FGF3 FGF10 FGF18 FGFR1 FGFR2 FGFR3 | Expressed during craniofacial development and can rarely harbor mutations that result in human clefting syndromes. | 184 | |
| SPRY1/SPRY2 | Loss of function mutations in FGFR1 cause a syndromic form of clefting. | 185 | |
| TBX10 | Ectopically expressed in dancer cleft lip and palate mutant mice. | 185 | |
| GABRB3 | β3 subunit of GABA receptor CL/P. | 62, 186, 6 | |
| GLI2 | Mutations in GLi2 cause holoprosencephaly-like features with cleft lip and palate. | 185 | |
| ISGF3G | Similar to IRF6. | 185 | |
| OTHER CANDIDATE GENES | |||
| SKI, FOXE1, JAG2, LHX8 | Rare causes of isolated cleft lip with or without cleft palate | 185 | |