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