Abstract
Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare severe cutaneous adverse reactions to drugs. Granulysin (GNLY) plays a key role in keratinocyte apoptosis during SJS/TEN pathophysiology. To determine if GNLY-encoding mutations might be related to the protein’s functional disturbances, contributing to SJS/TEN pathogenesis, we performed direct sequencing of GNLY’s coding region in a group of 19 Colombian SJS/TEN patients. A GNLY genetic screening was implemented in a group of 249 healthy individuals. We identified the c.11G > A heterozygous sequence variant in a TEN case, which creates a premature termination codon (PTC) (p.Trp4Ter). We show that a mutant protein is synthesised, possibly due to a PTC-readthrough mechanism. Functional assays demonstrated that the mutant protein was abnormally located in the nuclear compartment, potentially leading to a toxic effect. Our results argue in favour of GNLY non-synonymous sequence variants contributing to SJS/TEN pathophysiology, thereby constituting a promising, clinically useful molecular biomarker.
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Data availability statement
The data and the GNLY c.11G > A variant that support the findings of this study were submitted to a locus-specific database (https://databases.lovd.nl/shared/genes/GNLY).
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Acknowledgements
This study and Laissue´s Lab is supported by the Universidad del Rosario (Grant: CS/ABN062/GENIUROS 019).
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LC, CS, HM, AR, and AD performed the clinical study. DF, DS, OL, YS, and DB performed the in vitro assays. PL directed the study and wrote the paper. All authors revised and approved the final version of the manuscript.
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Fonseca, D.J., Caro, L.A., Sierra-Díaz, D.C. et al. Mutant GNLY is linked to Stevens–Johnson syndrome and toxic epidermal necrolysis. Hum Genet 138, 1267–1274 (2019). https://doi.org/10.1007/s00439-019-02066-w
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DOI: https://doi.org/10.1007/s00439-019-02066-w