1. Mutant GNLY is linked to Stevens-Johnson syndrome and toxic epidermal necrolysis.
- Author
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Fonseca DJ, Caro LA, Sierra-Díaz DC, Serrano-Reyes C, Londoño O, Suárez YC, Mateus HE, Bolívar-Salazar D, Ramírez AF, de-la-Torre A, and Laissue P
- Subjects
- Adolescent, Adult, Apoptosis, Biomarkers metabolism, Case-Control Studies, Child, Child, Preschool, Female, Genetic Predisposition to Disease, Humans, Infant, Male, Middle Aged, Mutant Proteins genetics, Young Adult, Antigens, Differentiation, T-Lymphocyte genetics, Keratinocytes pathology, Mutant Proteins metabolism, Mutation, Necrosis, Stevens-Johnson Syndrome genetics, Stevens-Johnson Syndrome pathology
- 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.
- Published
- 2019
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