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. 2024 Jun 27;31:64. doi: 10.1186/s12929-024-01054-1

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] [2832] 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 [3940] [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] [6769]

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