Table 1.
Autosomal dominant monogenic diseases caused by mutant secretory and membranal proteins
Genetic Disorder | Gene | Protein formation (Dimer/Oligomer) | Reported ER retention | Reported DN effect | Therapeutic strategies overcoming DN effects and cellular consequences |
---|---|---|---|---|---|
Skeletal and Connective Tissues Disorders | |||||
Marfan Syndrome (MFS) | FBN1 | Dimer | [24] | [25] |
Gene editing [26] TGF-β antagonists to block the excessive TGF-β signaling [27] |
Idiopathic short stature syndrome | NPR2 | Dimer | [28] | [28–32] | Recombinant growth hormone replacement therapy [33] |
Limb-girdle Muscular Dystrophy (LGMD-1C) | CAV3 | Oligomer | [34] | [34] |
Gene therapy: recombinant AAV1 vector-based therapy for various LGMD-related gene (Sarcoglycan, DYSF, and SGCB) stimulators [35] Small molecule correctors: lumacaftor and tezacaftor [36] |
Bethlem Myopathy Disorder | COL6A1, COL6A2 and COL6A3 | Heterotrimer | NR | [37] | Molecular modulators: cyclosporin A rescues the mitochondrial dysfunction and decreases apoptosis [38] |
Osteogenesis Imperfecta | COL1A1 and COL1A2 | Homotrimer | [39, 40] | [41] |
Signaling pathway modulators: Denosumab, Romosozumab, and Anti-TGF-β Antibodies [42] Bone marrow and stem cell transplantation [42] Gene therapy via antisense oligodeoxyribonucleotides; siRNA, short interfering RNA; CRISPR–Cas9 and hammerhead ribozymes [42] Counteraction of ER Stress and UPR (4-phenylbutyrate) [42] |
Ehlers-Danlos Syndrome | COL5A1 and COL5A2 | Heterotrimer | NR | [43] |
Gene therapy: Allele-specific siRNA knockdown [44] Signaling pathway modulators: Celiprolol (cardioselective β-blocker) [44] |
Stickler syndrome | COL2A1, COL11A1 and COL11A2 | Heterotrimer | [45] | [46] | NR |
Vascular Disorders | |||||
Hereditary Haemorrhagic telangiectasia type 1 (HHT1) | ENG | Dimer | [13] | [47] | ENG and ACVRL1 gene expression stimulator [48] |
Hereditary Haemorrhagic telangiectasia type 2 (HHT2) | ACVRL1 | Dimer | [16] | [49] |
FGF signaling modulation via beta-blockers: Etamsylate [48] Angiogenesis signaling pathways modulation: Bevacizumab, thalidomide, nintedanib, and anti-ANGPT2 antibodies [48] |
Pulmonary arterial hypertension (PAH) | BMPR2 | Dimer | [15] | [50] |
Counteraction of ER Stress and UPR (4-phenylbutyrate) [50] Targeting various PAH molecular pathways: 1) endothelin receptor signaling, 2) nitric oxide-sGC signaling, 3) prostacyclin replacement or receptor agonists, and 4) calcium channel blockers [51] |
Loeys-Dietz Syndrome (LDS) | TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2 and TGFB3 | Dimers | NR | [52] | Gene editing: correcting genetic mutations in TGFBR1 gene via CRISPR-Cas9 in human-derived iPSC [53] |
Long QT syndrome (LQTS) type 2 | KCNH2 | Dimer | [54] | [54] |
Gene therapy: single suppression-replacement of KCNH2 gene therapy using shRNA in iPSC- patient-derived cardiomyocyte [55] β-blocker medications [56] Pharmacological correction of the trafficking defect and ER retention using chaperones and channel blockers [57] |
Neurological Disorders | |||||
Generalized epilepsy with febrile seizures (GEFS +) | GABRG2 | Pentamer | [58] | [59] | Gene therapy; γ2 subunit gene (GABRG2) replacement therapy [58] |
spinocerebellar ataxias 13 | KCNC3 | Tetramer | [60] | [60] | Trafficking defect correction: Co-expression of the epidermal growth factor receptor (Egfr) with the DM KCNC3R423H effectively rescues the eye developmental defects (Drosophila model) [60] |
Neurofibromatosis Type 1 (NF1) | NF1 | Dimer | [61] | [61] |
Gene therapy: 1) Nonsense suppression using Aminoglycoside antibiotics to cause a read-through of nonsense mutations and restore the functional protein in short-term studies 2) Splice-blocking antisense oligonucleotides (ASOs) can effectively skip mutant exons in cultured cells with NF1 deep intronic mutations, restoring neurofibromin expression 3) recombinant rAAV carrying the WT NF1 [62] Targeting ER stress through a combination treatment of Hsp90 inhibitor and rapamycin immunosuppressant [62] |
DYT1 dystonia | TOR1A | oligomer | [63, 64] | [63, 64] |
Gene therapy: 1) Allele-specific targeting of mutant TOR1A by the compact CRISPR/NmCas9 system 2) Gene editing via CRISPR/Cas9 to repair the mutation site in the DYT- TOR1A gene and restore its normal function [65] |
Eye Disorders | |||||
Retinitis Pigmentosa (RP) | RHO | Dimer/Oligomer | [66] | [67–69] |
Blocking the gene product from the mutant allele through ribozymes [70] Posttranslational gene silencing via shRNA and RNAi [70] |
Primary open angle glaucoma (POAG) | MYOC | Oligomer | [71] | [72] |
Gene therapy: 1) knocking out MYOC via viral-mediated CRISPR/Cas9 [73] Inhibiting MYOC mRNA transcription or translation through siRNA and shRNA [73] Using chemical chaperones to reduce protein misfolding and increase mutant myocilin secretion [74] |
Wolfram syndrome (WS) | WFS1 | Monomer (WT) Aggregate (Mutant) | [75] | [75] |
Gene therapy: mutant allele replacement via CRISPR/Cas9 in patient iPSCs to create iPSC-derived organoids [76] Correct protein misfolding and stabilization: chemical and molecular chaperones: 4-phenylbutyric acid, tauroursodeoxycholic acid and sigma-1 receptor chaperone [76] Regulating ER calcium homeostasis using ER calcium stabilizers: Ibudilast and dantrolene [76] Targeting ER stress: Valproic acid and GLP-1R agonist like liraglutide [77] |
Serpinopathies | |||||
Antithrombin deficiency | SERPINC1 |
Monomer (WT) Aggregate (Mutant) |
[78] | [78] | NR |
Alpha-1-antitrypsin deficiency (AATD) | SERPINA1 |
Monomer (WT) Aggregate (Mutant) |
[79] | [79] |
Gene therapy: 1) Supplementation of the WT gene through viral transduction in fibroblasts derived from patients [80] 2) liver-directed rAAV-mediated gene augmentation [80] 3) mRNA silencing via specific RNAi (Fazirsiran) [81] |
Hereditary angioedema type 1 (HAE1) | SERPING1 |
Monomer (WT) Aggregate (Mutant) |
[81] | [81] | Gene therapy: WT SERPING1 gene supplementation via AAV vector [82] |
The table highlights the reported dominant-negative effects and ER-retention implicated in the molecular mechanisms of the listed diseases. It also highlights reported therapeutic strategies overcoming dominant negative effects and cellular consequences
NR Not reported, DN Dominant-negative