Nonsense Suppression Therapy: An Emerging Treatment for Hereditary Skin Diseases


  • Jiangfan Yu
  • Bingsi Tang
  • Xinglan He
  • Puyu Zou
  • Zhuotong Zeng Department of Dermatology, Second Xiangya Hospital of Central South University, Changsha 410011, China
  • Rong Xiao Department of Dermatology, Second Xiangya Hospital of Central South University, Changsha 410011, China



readthrough, aminoglycosides, PTC124, nonsense-mediated decay, suppressor tRNA, hereditary skin diseases


Nonsense mutations cause the premature termination of protein translation via premature termination codons (PTCs), leading to the synthesis of incomplete functional proteins and causing large numbers of genetic disorders. The emergence of nonsense suppression therapy is considered to be an effective method for the treatment of hereditary diseases, but its application in hereditary skin diseases is relatively limited. This review summarizes the current research status of nonsense suppression therapy for hereditary skin diseases, and discusses the potential opportunities and challenges of applying new technologies related to nonsense suppression therapy to dermatology. Further research is needed into the possible use of nonsense suppression therapy as a strategy for the safer and specific treatment of hereditary skin diseases.


Download data is not yet available.

Author Biographies

Jiangfan Yu

Department of Dermatology, Second Xiangya Hospital of Central South University

Zhuotong Zeng, Department of Dermatology, Second Xiangya Hospital of Central South University, Changsha 410011, China


Rong Xiao, Department of Dermatology, Second Xiangya Hospital of Central South University, Changsha 410011, China



Porter JJ, Heil CS, Lueck JD. Therapeutic promise of engineered nonsense suppressor tRNAs. Wiley Interdiscip Rev RNA 2021; 12: e1641. DOI:

Mendell JT, Dietz HC. When the message goes awry: disease-producing mutations that influence mRNA content and performance. Cell 2001; 107: 411-414. DOI:

Baradaran-Heravi A, Balgi AD, Hosseini-Farahabadi S, Choi K, Has C, Roberge M. Effect of small molecule eRF3 degraders on premature termination codon readthrough. Nucleic Acids Res 2021; 49: 3692-3708. DOI:

Lee HL, Dougherty JP. Pharmaceutical therapies to recode nonsense mutations in inherited diseases. Pharmacol Ther 2012; 136: 227-266. DOI:

Panchal RG, Wang S, McDermott J, Link CJ. Partial functional correction of xeroderma pigmentosum group A cells by suppressor tRNA. Hum Gene Ther 1999; 10: 2209-2219. DOI:

Frolova L, Le Goff X, Rasmussen HH, Cheperegin S, Drugeon G, Kress M, et al. A highly conserved eukaryotic protein family possessing properties of polypeptide chain release factor. Nature 1994; 372: 701-703. DOI:

Temple GF, Dozy AM, Roy KL, Kan YW. Construction of a functional human suppressor tRNA gene: an approach to gene therapy for beta-thalassaemia. Nature 1982; 296: 537-540. DOI:

Kiselev AV, Ostapenko OV, Rogozhkina EV, Kholod NS, Seit NA, Baranov AN, et al. Suppression of nonsense mutations in the Dystrophin gene by a suppressor tRNA gene. Mol Biol (Mosk) 2002; 36: 43-47. DOI:

Howard M, Frizzell RA, Bedwell DM. Aminoglycoside antibiotics restore CFTR function by overcoming premature stop mutations. Nat Med 1996; 2: 467-469. DOI:

Clancy JP, Bebok Z, Ruiz F, King C, Jones J, Walker L, et al. Evidence that systemic gentamicin suppresses premature stop mutations in patients with cystic fibrosis. Am J Respir Crit Care Med 2001; 163: 1683-1692. DOI:

Howard MT, Shirts BH, Petros LM, Flanigan KM, Gesteland RF, Atkins JF. Sequence specificity of aminoglycoside-induced stop codon readthrough: potential implications for treatment of Duchenne muscular dystrophy. Ann Neurol 2000; 48: 164-169.<164::AID-ANA5>3.0.CO;2-B DOI:<164::AID-ANA5>3.0.CO;2-B

Sossi V, Giuli A, Vitali T, Tiziano F, Mirabella M, Antonelli A, et al. Premature termination mutations in exon 3 of the SMN1 gene are associated with exon skipping and a relatively mild SMA phenotype. Eur J Hum Genet 2001; 9: 113-120. DOI:

Kaler SG, Tang J, Donsante A, Kaneski CR. Translational read-through of a nonsense mutation in ATP7A impacts treatment outcome in Menkes disease. Ann Neurol 2009; 65: 108-113. DOI:

Lai CH, Chun HH, Nahas SA, Mitui M, Gamo KM, Du L, et al. Correction of ATM gene function by aminoglycoside-induced read-through of premature termination codons. Proc Natl Acad Sci U S A 2004; 101: 15676-15681. DOI:

Fazzari M, Frasca A, Bifari F, Landsberger N. Aminoglycoside drugs induce efficient read-through of CDKL5 nonsense mutations, slightly restoring its kinase activity. Rna Biol 2019; 16: 1414-1423. DOI:

Keeling KM, Brooks DA, Hopwood JJ, Li P, Thompson JN, Bedwell DM. Gentamicin-mediated suppression of Hurler syndrome stop mutations restores a low level of alpha-L-iduronidase activity and reduces lysosomal glycosaminoglycan accumulation. Hum Mol Genet 2001; 10: 291-299. DOI:

Helip-Wooley A, Park MA, Lemons RM, Thoene JG. Expression of CTNS alleles: subcellular localization and aminoglycoside correction in vitro. Mol Genet Metab 2002; 75: 128-133. DOI:

Sangkuhl K, Schulz A, Rompler H, Yun J, Wess J, Schoneberg T. Aminoglycoside-mediated rescue of a disease-causing nonsense mutation in the V2 vasopressin receptor gene in vitro and in vivo. Hum Mol Genet 2004; 13: 893-903. DOI:

Grayson C, Chapple JP, Willison KR, Webster AR, Hardcastle AJ, Cheetham ME. In vitro analysis of aminoglycoside therapy for the Arg120stop nonsense mutation in RP2 patients. J Med Genet 2002; 39: 62-67. DOI:

Moosajee M, Tracey-White D, Smart M, Weetall M, Torriano S, Kalatzis V, et al. Functional rescue of REP1 following treatment with PTC124 and novel derivative PTC-414 in human choroideremia fibroblasts and the nonsense-mediated zebrafish model. Hum Mol Genet 2016; 25: 3416-3431. DOI:

Moosajee M, Gregory-Evans K, Ellis CD, Seabra MC, Gregory-Evans CY. Translational bypass of nonsense mutations in zebrafish rep1, pax2.1 and lamb1 highlights a viable therapeutic option for untreatable genetic eye disease. Hum Mol Genet 2008; 17: 3987-4000. DOI:

Rebibo-Sabbah A, Nudelman I, Ahmed ZM, Baasov T, Ben-Yosef T. In vitro and ex vivo suppression by aminoglycosides of PCDH15 nonsense mutations underlying type 1 Usher syndrome. Hum Genet 2007; 122: 373-381. DOI:

Nishimoto K, Iijima K, Shirakawa T, Kitagawa K, Satomura K, Nakamura H, et al. PAX2 gene mutation in a family with isolated renal hypoplasia. J Am Soc Nephrol 2001; 12: 1769-1772. DOI:

Richardson R, Smart M, Tracey-White D, Webster AR, Moosajee M. Mechanism and evidence of nonsense suppression therapy for genetic eye disorders. Exp Eye Res 2017; 155: 24-37. DOI:

Isidor B, Lindenbaum P, Pichon O, Bezieau S, Dina C, Jacquemont S, et al. Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis. Nat Genet 2011; 43: 306-308. DOI:

Castaman G, Bertoncello K, Bernardi M, Eikenboom JC, Budde U, Rodeghiero F. Autosomal recessive von Willebrand disease associated with compound heterozygosity for a novel nonsense mutation (2908 del C) and the missense mutation C2362F: definite evidence for the non-penetrance of the C2362F mutation. Am J Hematol 2007; 82: 376-380. DOI:

Bezzerri V, Cipolli M. Shwachman-Diamond syndrome: molecular mechanisms and current perspectives. Mol Diagn Ther 2019; 23: 281-290. DOI:

Dorin JR, Farley R, Webb S, Smith SN, Farini E, Delaney SJ, et al. A demonstration using mouse models that successful gene therapy for cystic fibrosis requires only partial gene correction. Gene Ther 1996; 3: 797-801.

Krause KM, Serio AW, Kane TR, Connolly LE. Aminoglycosides: an overview. Cold Spring Harb Perspect Med 2016; 6: a027029. DOI:

Keeling KM, Wang D, Conard SE, Bedwell DM. Suppression of premature termination codons as a therapeutic approach. Crit Rev Biochem Mol Biol 2012; 47: 444-463. DOI:

Schueren F, Thoms S. Functional translational readthrough: a systems biology perspective. Plos Genet 2016; 12: e1006196. DOI:

Leier A, Bedwell DM, Chen AT, Dickson G, Keeling KM, Kesterson RA, et al. Mutation-directed therapeutics for neurofibromatosis Type I. Mol Ther Nucleic Acids 2020; 20: 739-753. DOI:

McHugh DR, Cotton CU, Hodges CA. Synergy between readthrough and nonsense mediated decay inhibition in a murine model of cystic fibrosis nonsense mutations. Int J Mol Sci 2020; 22: 344. DOI:

Prokhorova I, Altman RB, Djumagulov M, Shrestha JP, Urzhumtsev A, Ferguson A, et al. Aminoglycoside interactions and impacts on the eukaryotic ribosome. Proc Natl Acad Sci U S A 2017; 114: e10899-e10908. DOI:

Baradaran-Heravi A, Niesser J, Balgi AD, Choi K, Zimmerman C, South AP, et al. Gentamicin B1 is a minor gentamicin component with major nonsense mutation suppression activity. Proc Natl Acad Sci U S A 2017; 114: 3479-3484. DOI:

Pasmooij A. Topical gentamicin for the treatment of genetic skin diseases. J Invest Dermatol 2018; 138: 731-734. DOI:

Linde L, Kerem B. Introducing sense into nonsense in treatments of human genetic diseases. Trends Genet 2008; 24: 552-563. DOI:

Dabrowski M, Bukowy-Bieryllo Z, Zietkiewicz E. Advances in therapeutic use of a drug-stimulated translational readthrough of premature termination codons. Mol Med 2018; 24: 25. DOI:

Nudelman I, Rebibo-Sabbah A, Cherniavsky M, Belakhov V, Hainrichson M, Chen F, et al. Development of novel aminoglycoside (NB54) with reduced toxicity and enhanced suppression of disease-causing premature stop mutations. J Med Chem 2009; 52: 2836-2845. DOI:

Hainrichson M, Nudelman I, Baasov T. Designer aminoglycosides: the race to develop improved antibiotics and compounds for the treatment of human genetic diseases. Org Biomol Chem 2008; 6: 227-239. DOI:

Hirawat S, Welch EM, Elfring GL, Northcutt VJ, Paushkin S, Hwang S, et al. Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers. J Clin Pharmacol 2007; 47: 430-444. DOI:

Campofelice A, Lentini L, Di Leonardo A, Melfi R, Tutone M, Pace A, et al. Strategies against nonsense: oxadiazoles as translational readthrough-inducing drugs (TRIDs). Int J Mol Sci 2019; 20: 3329. DOI:

Du M, Liu X, Welch EM, Hirawat S, Peltz SW, Bedwell DM. PTC124 is an orally bioavailable compound that promotes suppression of the human CFTR-G542X nonsense allele in a CF mouse model. Proc Natl Acad Sci U S A 2008; 105: 2064-2069. DOI:

Lentini L, Melfi R, Di Leonardo A, Spinello A, Barone G, Pace A, et al. Toward a rationale for the PTC124 (Ataluren) promoted readthrough of premature stop codons: a computational approach and GFP-reporter cell-based assay. Mol Pharm 2014; 11: 653-664. DOI:

Roy B, Friesen WJ, Tomizawa Y, Leszyk JD, Zhuo J, Johnson B, et al. Ataluren stimulates ribosomal selection of near-cognate tRNAs to promote nonsense suppression. Proc Natl Acad Sci U S A 2016; 113: 12508-12513. DOI:

McElroy SP, Nomura T, Torrie LS, Warbrick E, Gartner U, Wood G, et al. A lack of premature termination codon read-through efficacy of PTC124 (Ataluren) in a diverse array of reporter assays. Plos Biol 2013; 11: e1001593. DOI:

Du L, Damoiseaux R, Nahas S, Gao K, Hu H, Pollard JM, et al. Nonaminoglycoside compounds induce readthrough of nonsense mutations. J Exp Med 2009; 206: 2285-2297. DOI:

Kayali R, Ku JM, Khitrov G, Jung ME, Prikhodko O, Bertoni C. Read-through compound 13 restores dystrophin expression and improves muscle function in the mdx mouse model for Duchenne muscular dystrophy. Hum Mol Genet 2012; 21: 4007-4020. DOI:

Du L, Jung ME, Damoiseaux R, Completo G, Fike F, Ku JM, et al. A new series of small molecular weight compounds induce read through of all three types of nonsense mutations in the ATM gene. Mol Ther 2013; 21: 1653-1660. DOI:

Friesen WJ, Trotta CR, Tomizawa Y, Zhuo J, Johnson B, Sierra J, et al. The nucleoside analog clitocine is a potent and efficacious readthrough agent. RNA 2017; 23: 567-577. DOI:

Arakawa M, Shiozuka M, Nakayama Y, Hara T, Hamada M, Kondo S, et al. Negamycin restores dystrophin expression in skeletal and cardiac muscles of mdx mice. J Biochem 2003; 134: 751-758. DOI:

Thompson J, Pratt CA, Dahlberg AE. Effects of a number of classes of 50S inhibitors on stop codon readthrough during protein synthesis. Antimicrob Agents Chemother 2004; 48: 4889-4891. DOI:

Lykke-Andersen S, Jensen TH. Nonsense-mediated mRNA decay: an intricate machinery that shapes transcriptomes. Nat Rev Mol Cell Biol 2015; 16: 665-677. DOI:

Brogna S, Wen J. Nonsense-mediated mRNA decay (NMD) mechanisms. Nat Struct Mol Biol 2009; 16: 107-113. DOI:

Azzalin CM, Lingner J. The human RNA surveillance factor UPF1 is required for S phase progression and genome stability. Curr Biol 2006; 16: 433-439. DOI:

Lueck JD, Yoon JS, Perales-Puchalt A, Mackey AL, Infield DT, Behlke MA, et al. Engineered transfer RNAs for suppression of premature termination codons. Nat Commun 2019; 10: 822. DOI:

Buvoli M, Buvoli A, Leinwand LA. Suppression of nonsense mutations in cell culture and mice by multimerized suppressor tRNA genes. Mol Cell Biol 2000; 20: 3116-3124. DOI:

Zhou Y, Jiang Q, Takahagi S, Shao C, Uitto J. Premature termination codon read-through in the ABCC6 gene: potential treatment for pseudoxanthoma elasticum. J Invest Dermatol 2013; 133: 2672-2677. DOI:

Ohguchi Y, Nomura T, Suzuki S, Takeda M, Miyauchi T, Mizuno O, et al. Gentamicin-induced readthrough and nonsense-mediated mRNA decay of SERPINB7 nonsense mutant transcripts. J Invest Dermatol 2018; 138: 836-843. DOI:

Li Y, Yu X, Pan C, Wang Y, Han J, Yao Z, et al. Effect of gentamicin ointment in patients with nagashima-type palmoplantar keratosis: a double-blind vehicle-controlled study. Acta Derm Venereol 2021; 101: adv00392. DOI:

Woodley DT, Cogan J, Hou Y, Lyu C, Marinkovich MP, Keene D, et al. Gentamicin induces functional type VII collagen in recessive dystrophic epidermolysis bullosa patients. J Clin Invest 2017; 127: 3028-3038. DOI:

Atanasova VS, Jiang Q, Prisco M, Gruber C, Pinon HJ, Chen M, et al. Amlexanox enhances premature termination codon read-through in COL7A1 and expression of full length Type VII collagen: potential therapy for recessive dystrophic epidermolysis bullosa. J Invest Dermatol 2017; 137: 1842-1849. DOI:

Cogan J, Weinstein J, Wang X, Hou Y, Martin S, South AP, et al. Aminoglycosides restore full-length type VII collagen by overcoming premature termination codons: therapeutic implications for dystrophic epidermolysis bullosa. Mol Ther 2014; 22: 1741-1752. DOI:

Kellermayer R, Szigeti R, Keeling KM, Bedekovics T, Bedwell DM. Aminoglycosides as potential pharmacogenetic agents in the treatment of Hailey-Hailey disease. J Invest Dermatol 2006; 126: 229-231. DOI:

Kuschal C, DiGiovanna JJ, Khan SG, Gatti RA, Kraemer KH. Repair of UV photolesions in xeroderma pigmentosum group C cells induced by translational readthrough of premature termination codons. Proc Natl Acad Sci U S A 2013; 110: 19483-19488. DOI:

Satokata I, Tanaka K, Okada Y. Molecular basis of group A xeroderma pigmentosum: a missense mutation and two deletions located in a zinc finger consensus sequence of the XPAC gene. Hum Genet 1992; 88: 603-607. DOI:

Peled A, Samuelov L, Sarig O, Bochner R, Malki L, Pavlovsky M, et al. Treatment of hereditary hypotrichosis simplex of the scalp with topical gentamicin. Br J Dermatol 2020; 183: 114-120. DOI:

Morais P, Adachi H, Yu YT. Suppression of nonsense mutations by new emerging technologies. Int J Mol Sci 2020; 21: 4394. DOI:



How to Cite

Yu, J., Tang, B., He, X. ., Zou, P. ., Zeng, Z. ., & Xiao, R. (2022). Nonsense Suppression Therapy: An Emerging Treatment for Hereditary Skin Diseases. Acta Dermato-Venereologica, 102, adv00658.