Treatment of hereditary hypotrichosis simplex of the scalp with topical gentamicin.
Journal
The British journal of dermatology
ISSN: 1365-2133
Titre abrégé: Br J Dermatol
Pays: England
ID NLM: 0004041
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
accepted:
15
11
2019
pubmed:
21
11
2019
medline:
15
5
2021
entrez:
21
11
2019
Statut:
ppublish
Résumé
Hypotrichosis simplex of the scalp (HSS) is characterized by progressive loss of scalp hair that results in almost complete baldness at a young age. HSS is often caused by dominant nonsense mutations in CDSN encoding corneodesmosin, leading to the formation of an amyloid-like material, which interferes with normal hair follicle cycle. As gentamicin has been shown to mediate ribosomal read-through, we aimed to ascertain its therapeutic efficacy in a small series of patients carrying a recurrent mutation in CDSN . We used a green fluorescence reporter assay system, confocal microscopy and Western blot analysis to ascertain in vitro the ability of gentamicin to induce translational read-through across a causative CDSN mutation. Using a reporter assay, we initially showed that gentamicin induces read-through activity across an HSS-causing nonsense mutation. Gentamicin was further shown to rescue corneodesmosin translation in primary keratinocytes obtained from a patient with HSS. To validate the in vitro data, we conducted a pilot clinical trial where the scalp of four patients was treated topically with gentamicin for 6 months, demonstrating significant improvement as ascertained by the Severity of Alopecia Tool score. Our findings indicate that topical gentamicin should be considered as a potential therapeutic modality in HSS. What's already known about this topic? Hypotrichosis simplex of the scalp (HSS) is caused by nonsense mutations in CDSN encoding corneodesmosin. The mutant corneodesmosin has been hypothesized to be toxic to the hair follicles, leading to hypotrichosis. Disorders caused by nonsense mutations are amenable to ribosomal read-through using gentamicin. What does this study add? Gentamicin enhanced read-through activity and promoted full-length corneodesmosin synthesis in primary keratinocytes derived from patients carrying a nonsense mutation in CDSN. Topical treatment with gentamicin was found to rescue the hypotrichosis phenotype partially in four patients with HSS. What is the translational message? Topical gentamicin should be considered as a potential treatment for HSS.
Sections du résumé
BACKGROUND
Hypotrichosis simplex of the scalp (HSS) is characterized by progressive loss of scalp hair that results in almost complete baldness at a young age. HSS is often caused by dominant nonsense mutations in CDSN encoding corneodesmosin, leading to the formation of an amyloid-like material, which interferes with normal hair follicle cycle.
OBJECTIVES
As gentamicin has been shown to mediate ribosomal read-through, we aimed to ascertain its therapeutic efficacy in a small series of patients carrying a recurrent mutation in CDSN .
METHODS
We used a green fluorescence reporter assay system, confocal microscopy and Western blot analysis to ascertain in vitro the ability of gentamicin to induce translational read-through across a causative CDSN mutation.
RESULTS
Using a reporter assay, we initially showed that gentamicin induces read-through activity across an HSS-causing nonsense mutation. Gentamicin was further shown to rescue corneodesmosin translation in primary keratinocytes obtained from a patient with HSS. To validate the in vitro data, we conducted a pilot clinical trial where the scalp of four patients was treated topically with gentamicin for 6 months, demonstrating significant improvement as ascertained by the Severity of Alopecia Tool score.
CONCLUSIONS
Our findings indicate that topical gentamicin should be considered as a potential therapeutic modality in HSS. What's already known about this topic? Hypotrichosis simplex of the scalp (HSS) is caused by nonsense mutations in CDSN encoding corneodesmosin. The mutant corneodesmosin has been hypothesized to be toxic to the hair follicles, leading to hypotrichosis. Disorders caused by nonsense mutations are amenable to ribosomal read-through using gentamicin. What does this study add? Gentamicin enhanced read-through activity and promoted full-length corneodesmosin synthesis in primary keratinocytes derived from patients carrying a nonsense mutation in CDSN. Topical treatment with gentamicin was found to rescue the hypotrichosis phenotype partially in four patients with HSS. What is the translational message? Topical gentamicin should be considered as a potential treatment for HSS.
Substances chimiques
CDSN protein, human
0
Gentamicins
0
Glycoproteins
0
Intercellular Signaling Peptides and Proteins
0
Types de publication
Clinical Trial
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
114-120Subventions
Organisme : Blavatnik Family Foundation
Pays : International
Organisme : German-Israeli Foundation for Scientific Research and Development
ID : I-1443-422.13
Pays : International
Organisme : Ram family foundation
Pays : International
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2019 British Association of Dermatologists.
Références
Levy-Nissenbaum E , Betz RC , Frydman M et al. Hypotrichosis simplex of the scalp is associated with nonsense mutations in CDSN encoding corneodesmosin. Nat Genet 2003; 34:151-3.
Kazantseva A , Goltsov A , Zinchenko R et al. Human hair growth deficiency is linked to a genetic defect in the phospholipase gene LIPH . Science 2006; 314:982-5.
Pasternack SM , Refke M , Paknia E et al. Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal-dominant hypotrichosis simplex. Am J Hum Genet 2013; 92:81-7.
Romano M-T , Tafazzoli A , Mattern M et al. Bi-allelic mutations in lss, encoding lanosterol synthase, cause autosomal-recessive hypotrichosis simplex. Am J Hum Genet 2018; 103:777-85.
Shimomura Y , Agalliu D , Vonica A et al. APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex. Nature 2010; 464:1043-7.
Shimomura Y , Wajid M , Ishii Y et al. Disruption of P2RY5, an orphan G protein-coupled receptor, underlies autosomal recessive woolly hair. Nat Genet 2008; 40:335-9.
Zernov NV , Skoblov MY , Marakhonov AV et al. Autosomal recessive hypotrichosis with woolly hair caused by a mutation in the keratin 25 gene expressed in hair follicles. J Invest Dermatol 2016; 136:1097-105.
Huang H , Sun J , Fu L et al. A novel insertion mutation of CDSN responsible for hypotrichosis simplex of scalp in a Chinese family. Clin Exp Dermatol 2018; 43:722-3.
Mendell JT , Dietz HC . When the message goes awry: disease-producing mutations that influence mRNA content and performance. Cell 2001; 107:411-14.
Mort M , Ivanov D , Cooper DN , Chuzhanova NA . A meta-analysis of nonsense mutations causing human genetic disease. Hum Mutat 2008; 29:1037-47.
Kuzmiak HA , Maquat LE . Applying nonsense-mediated mRNA decay research to the clinic: progress and challenges. Trends Mol Med 2006; 12:306-16.
Nicholson P , Yepiskoposyan H , Metze S et al. Nonsense-mediated mRNA decay in human cells: mechanistic insights, functions beyond quality control and the double-life of NMD factors. Cell Mol Life Sci 2009; 67:677-700.
Rebbapragada I , Lykke-Andersen J . Execution of nonsense-mediated mRNA decay: what defines a substrate? Curr Opin Cell Biol 2009; 21:394-402.
Khajavi M , Inoue K , Lupski JR . Nonsense-mediated mRNA decay modulates clinical outcome of genetic disease. Eur J Hum Genet 2006; 14:1074-81.
Inoue K , Khajavi M , Ohyama T et al. Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations. Nat Genet 2004; 36:361-9.
Bidou L , Allamand V , Rousset JP , Namy O . Sense from nonsense: therapies for premature stop codon diseases. Trends Mol Med 2012; 18:679-88.
Manuvakhova M , Keeling KIM , Bedwell DM . Aminoglycoside antibiotics mediate context-dependent suppression of termination codons in a mammalian translation system. RNA 2000; 6:1044-55.
Sabbavarapu NM , Shavit M , Degani Y et al. Design of novel aminoglycoside derivatives with enhanced suppression of diseases-causing nonsense mutations. ACS Med Chem Lett 2016; 7:418-23.
Zingman LV , Park S , Olson TM et al. Aminoglycoside-induced translational read-through in disease: overcoming nonsense mutations by pharmacogenetic therapy. Clin Pharmacol Ther 2007; 81:99-103.
Halvey PJ , Liebler DC , Slebos RJC . A reporter system for translational readthrough of stop codons in human cells. Febs Open Bio 2012; 2:56-9.
Hermann T . Aminoglycoside antibiotics: old drugs and new therapeutic approaches. Cell Mol Life Sci 2007; 64:1841-52.
Lincoln V , Cogan J , Hou Y et al. Gentamicin induces LAMB3 nonsense mutation readthrough and restores functional laminin 332 in junctional epidermolysis bullosa. Proc Natl Acad Sci USA 2018; 115:E6536-45.
Greenberg LH , Momary H . Audiotoxicity and nephrotoxicity due to orally administered neomycin. JAMA 1965; 194:827-8.
Ruben RJ , Daly JF . Neomycin ototoxicity and nephrotoxicity. Laryngoscope 1968; 78:1734-7.
Bennett WM . Mechanisms of aminoglycoside nephrotoxicity. Clin Exp Pharmacol Physiol 1989; 16:1-6.
El Bakri F , Pallett A , Smith AG , Duncombe AS . Ototoxicity induced by once-daily gentamicin. Lancet 1998; 351:1407-8.
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.
Samuelov L , Sarig O , Harmon RM et al. Desmoglein 1 deficiency results in severe dermatitis, multiple allergies and metabolic wasting. Nat Genet 2013; 45:1244-8.
Olsen EA , Hordinsky MK , Price VH et al. Alopecia areata investigational assessment guidelines-part II. J Am Acad Dermatol 2004; 51:440-7.
Bokhari L , Sinclair R . Treatment of alopecia universalis with topical Janus kinase inhibitors - a double blind, placebo, and active controlled pilot study. Int J Dermatol 2018; 57:1464-70.
Özdemir M , Balevi A . Bilateral half-head comparison of 1% anthralin ointment in children with alopecia areata. Pediatr Dermatol 2017; 34:128-32.
Talpur R , Vu J , Bassett R et al. Phase I/II randomized bilateral half-head comparison of topical bexarotene 1% gel for alopecia areata. J Am Acad Dermatol 2009; 61:592.e1-9.
Alves R , Grimalt R . Hair loss in children. Curr Probl Dermatol 2015; 47:55-66.
Aschenbeck KA , McFarland SL , Hordinsky MK et al. Importance of group therapeutic support for family members of children with alopecia areata: a cross-sectional survey study. Pediatr Dermatol 2017; 34:427-32.
Xu L , Liu KX , Senna MM . A practical approach to the diagnosis and management of hair loss in children and adolescents. Front Med (Lausanne) 2017; 4:112.
Kellermayer R , Szigeti R , Keeling KM et al. Aminoglycosides as potential pharmacogenetic agents in the treatment of Hailey-Hailey disease. J Invest Dermatol 2006; 126:229-31.
Woodley DT , Cogan J , Hou Y et al. Gentamicin induces functional type VII collagen in recessive dystrophic epidermolysis bullosa patients. J Clin Invest 2017; 127:3028-38.
Ohguchi Y , Nomura T , Suzuki S et al. Gentamicin-induced readthrough and nonsense-mediated mRNA decay of SERPINB7 nonsense mutant transcripts. J Invest Dermatol 2018; 138:836-43.
Liippo J , Lammintausta K . Positive patch test reactions to gentamicin show sensitization to aminoglycosides from topical therapies, bone cements, and from systemic medication. Contact Dermatitis 2008; 59:268-72.