Table 1.
Summary of the genetic diseases in which connective tissue molecular components are affected, their causative gene with OMIN and ORPHAN numbers, the radical species involved and reported therapeutic approaches.
| Molecular Target | Genetic Disease | Gene | Omim Number |
Orphan Number |
Redox-Associated Dysfunction | Antioxidant or Antioxidant-Related Therapeutics |
|---|---|---|---|---|---|---|
| Collagen Fibers | Alport syndrome | COL4A3 | 203780 | 88919 | Urinary HO-1 and H2O2; mitochondrial ROS; reduction GSH:GSSSG ratio; mitochondrial respiration dysfunction | Anti-miR 21. Osteopontin deficiency |
| COL4A4 | 104200 | 88918 | ||||
| COL4A5 | 301050 | 88917 | ||||
| Bethlem myopathy (BMP) |
COL6A1
COL6A2 COL6A3 |
158810 | 610 | Augmented mitochondrial MAO-induced ROS | Inhibition of cyclophilin D | |
| Ullrich congenital muscular dystrophy (UCMD) | 254090 | 75840 | ||||
| Myosclerosis myopathy (MSMP) | 255600 | 289380 | ||||
| Fuchs syndrome (FS) | COL8A2 | 136800 | 98974 | Overall ROS increase; SOD, catalase, Glutathione peroxidase and reductase depletion; downregulation of peroxiredoxin antioxidants; | Elamitrepide (avoids peroxidation of cardiolipin) | |
| Collagen XV deficiencies | COL15A1 | 120325 (GEN) | - | Overall ROS increase; mitochondrial dysfunctions; | Cyclosporine A; losartan |
|
| Elastic Fibers | Supravalvular aortic stenosis (SAS) | ELN | 185500 | 3193 | Increased ROS by NCF1 overexpression | |
| Williams-Beuren syndrome (WBS) | 1.55–1.83 Mb at chromosomal band 7q11.23 deletion (including ELN) | 194050 | 904 | One copy deletion of NCF1; increased superoxide anion; increased nuclear levels of NFR2; mitochondrial dysfunction by DNAJC30 loss; increased aortic nNOS expression and activity | Reduction of Ncf1 expression; apocynin; losartan; epigalloctechnin-3-gallate (EGCG) |
|
| Cutis laxa (CL) | ELN | 123700 | 90348 | |||
| FBLN4 | 614437 | 90349 | ||||
| FBLN5 | 219100 | 90349 | ||||
| LTBP4 | 61377 | - | ||||
| ATP7A | 304150 | 198 | ||||
| ATP6V0A2 | 219200 | 357058 | ||||
| PYCR1 | 612940 | 357064 | Mitochondrial antioxidant unbalance | |||
| ALDH18A1 | 219150 | 35664 | ||||
| Aortic tortuosity syndrome (ATS) | SLC2A10 | 208050 | 3342 | Dehydroascorbate transport dysfunction-induced ROS increase | ||
| Marfan syndrome (MFS) | FBN1 | 154700 | 558 | Overall increased ROS levels; increased H2O2 by LOX dysfunction and/or NOX4 overexpression; increased NO breakdown; increased aortic iNOS expression; increased peroxynitrite and 3′-nitrotyrosine residues; glutathione reduction |
Losartan; Indometathin; Apocynin; Cobinamide; N-acetylcysteine; Resveratrol; |
|
| Weill-Marchesani syndrome (WMS) | FBN1 | 608328 | 3449 | Increased plasma levels of LPO and NO; reduced antioxidant capabilities; | ||
| Systemic sclerosis (SSc) | Association with FBN1 | 181750 | 90291 | Increased circulating and tissue ROS levels; NADPH oxidase (NOX2 and NOX4) overexpression | Sindenafil; Kaempferol: EGCG; Tocilizumab; Hydrogen sulfide; Dimethyl fumarate | |
| Loeys-Dietz syndrome (LDS) | TGFBR1 | 609192 | 60030 | Reduced plasma levels of general antioxidant systems increased SOD and XO activities reduced mitochondrial respiration |
||
| TGFBR2 | 610168 | 60030 | ||||
| SMAD3 | 613795 | 91387-284984 | ||||
| TGFB2 | 614816 | 91387 | ||||
| TGFB3 | 615582 | 91387 | ||||
| Ground Substance | Mucopolysaccharidosis (MPS) I | IDUA |
607014 60716 |
579 93473-93476-93474 |
Overall increased ROS; mitochondrial dysfunction; increased lipid peroxidation; SOD and catalase dysfunctions; |
Enzyme replacement therapy. |
| MPS II | IDS |
309900 |
580 217093-217085 |
Anomalous mitochondrial pattern | Enzyme replacement therapy. Vitamin E |
|
| MPS III |
SGSH NAGLU HGSNAT GNS |
252900 252920 252930 252940 |
581 79269 79270 79271 79272 |
NOX1 and NOX2 upregulation; increased H2O2 and peroxynitrite; |
Coenzyme Q10; Antioxidant cocktail (α-tocopherol, N-acetylcysteine and α-lipoic acid) |
|
| MPS IV |
GALNS GLB1 |
253000 253010 |
582 309297 309310 |
Reduction of antioxidant defense systems together with oxidative-induced DNA, lipid, and protein damage | Enzyme replacement therapy | |
| MPS VI | ARSB | 253200 | 583 | release of NO | Enzyme replacement therapy | |
| MPS VII | GUSB | 253220 | 584 | release of NO |