Aminoglycosides as Potential Pharmacogenetic Agents in the Treatment of Hailey–Hailey Disease

Kellermayer, Richárd; Szigeti, Réka; Keeling, Kim M.; Bedekovics, Tibor; Bedwell, David M.

doi:10.1038/sj.jid.5700031

Cited by 66 publications

(60 citation statements)

References 19 publications

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“…Shiozuka et al (42) demonstrated that topically applied 0.1% gentamicin cream to shaved mdx dystrophin mouse skin induces readthrough of UGA. Similarly, one patient with Hailey-Hailey disease with a PTC in the ATP2C1 gene responded better to topical 0.1% gentamicin than to a boric acid control (43). The expressed XPC protein after treatment with less toxic small molecule nonaminoglycosides BZ16 and RTC14 might be as efficient in inducing DNA repair as aminoglycosideinduced XPC expression.…”

Section: Discussionmentioning

confidence: 99%

Repair of UV photolesions in xeroderma pigmentosum group C cells induced by translational readthrough of premature termination codons

Kuschal

DiGiovanna

Khan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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About 12% of human genetic disorders involve premature termination codons (PTCs). Aminoglycoside antibiotics have been proposed for restoring full-length proteins by readthrough of PTC. To assess the efficiency of readthrough, we selected homozygous and compound heterozygous skin fibroblasts from xeroderma pigmentosum (XP) patients with different PTCs in the XPC DNA repair gene. XP patients have a nucleotide excision repair defect and a 10,000-fold increased risk of UV-induced skin cancer. In six of eight PTC-containing XP-C cells, treatment with Geneticin and gentamicin resulted in (i) stabilized XPC-mRNA, which would have been degraded by nonsense-mediated decay; (ii) increased expression of XPC protein that localized to UV-damaged sites; (iii) recruitment of XPB and XPD proteins to UV DNA damage sites; and (iv) increased repair of 6-4 photoproducts and cyclobutane pyrimidine dimers. Expression of PTC in a transfected vector revealed that readthrough depends on the PTC sequence and its location within the gene. This sensitive DNA repair assay system demonstrates the complexity of response to PTC readthrough inducers. The efficiency of aminoglycoside-mediated readthrough depends on the type and copy number of PTC, the downstream 4+ nucleotide, and the location within the exon. Treatment with small-molecule nonaminoglycoside compounds (PTC124, BZ16, or RTC14) resulted in similarly increased XPC mRNA expression and photoproduct removal with less toxicity than with the aminoglycosides. Characterizing PTC structure and parameters governing effective PTC readthrough may provide a unique prophylactic therapy for skin cancer prevention in XP-C patients.readthrough compounds | UV radiation

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Section: Discussionmentioning

confidence: 99%

Repair of UV photolesions in xeroderma pigmentosum group C cells induced by translational readthrough of premature termination codons

Kuschal

DiGiovanna

Khan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Substitution of a PTC for a near-cognate amino acid can be induced by administering aminoglycosides, negamycin [36,37], or PTC124 [38], or by depleting termination factors [39,40]. Substituting a PTC with the cognate amino acid is also possible using suppressor-tRNAs [41].…”

Section: Keymentioning

confidence: 99%

Cancer syndromes and therapy by stop-codon readthrough

Bordeira–Carriço¹,

Pêgo²,

Santos³

et al. 2012

Trends in Molecular Medicine

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“…Topical aminoglycosides may have the added benefit of reversing the effects of pathogenic nonsense mutations by inducing read through of stop mutations. 22 Low-dose oral tetracyclines, erythromycin or flucloxacillin should also be entertained. Oral treatment of herpes simplex should be considered in patients with unresponsive, painful disease.…”

Section: Treatmentmentioning

confidence: 99%

Hailey Hailey disease-a rare case report

et al. 2016

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Hailey-Hailey disease is an autosomal dominant acantholytic disorder relatively uncommon in India. It is characterized by painful, pruritic, foul smelling vesicles and bullous lesions with erosions in intertriginous areas such as the neck, axillae, inframammary areas and groin. The defect in ATPC2 gene leads to calcium channel dysfunction which results in defect in epidermis. Fungal infection, intertrigo, psoriasis, extramammary Paget's disease, acanthosis nigricans, pemphigus vegetans and Darier's disease are some of the dermatosis from which it needs to be differentiated. Histopathology has a key role in diagnosis of Hailey-Hailey disease with characteristic ‘dilapidated brick wall' appearance. Hailey-Hailey disease can be easily misdiagnosed by general physicians due to lack of knowledge of this uncommon disease as it resembles dermatosis involving intertriginous areas. Due to its relapsing and remitting course there is a need to have effective treatment options. We report a case of 45 year old middle aged female who presented with on and off itchy papules & vesicles over right inframammmary region around the umbilicus & medial aspect of right thigh. Skin biopsy revealed a diagnosis of Hailey-Hailey disease. This case is being reported due to its rare occurrence.

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Aminoglycosides as Potential Pharmacogenetic Agents in the Treatment of Hailey–Hailey Disease

Cited by 66 publications

References 19 publications

Repair of UV photolesions in xeroderma pigmentosum group C cells induced by translational readthrough of premature termination codons

Repair of UV photolesions in xeroderma pigmentosum group C cells induced by translational readthrough of premature termination codons

Cancer syndromes and therapy by stop-codon readthrough

Hailey Hailey disease-a rare case report

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