Mutant GNLY is linked to Stevens–Johnson syndrome and toxic epidermal necrolysis

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. © 2019, Springer-Verlag GmbH Germany, part of Springer Nature.

• Fecha de publicación: 2019
• Institución: Universidad del Rosario
• Repositorio: Repositorio EdocUR - U. Rosario
• Idioma: eng
• OAI Identifier: oai:repository.urosario.edu.co:10336/24215
• Acceso en línea: https://doi.org/10.1007/s00439-019-02066-w; https://repository.urosario.edu.co/handle/10336/24215
• Palabra clave: Carbamazepine; Cefalexin; Cocodamol; Contrast medium; Cotrimoxazole; Granulysin; Lamotrigine; Metoclopramide; Phenytoin; Pyrimethamine plus sulfadoxine; Sulfonamide; Biological marker; Mutant protein; T lymphocyte antigen; Adult; Animal cell; Article; Cellular distribution; Child; Cho cell line; Clinical article; Codon; Computer model; Female; Gene frequency; Gene mutation; Gene sequence; Heterozygote; Human; Male; Middle aged; Nonhuman; Nucleotide sequence; Pathogenesis; Pathophysiology; Preschool child; Priority journal; Protein localization; Sanger sequencing; School child; Stevens johnson syndrome; Toxic epidermal necrolysis; Urtica dioica; Western blotting; Young adult; Adolescent; Apoptosis; Case control study; Genetic predisposition; Genetics; Infant; Keratinocyte; Metabolism; Mutation; Necrosis; Pathology; Stevens johnson syndrome; Adolescent; Adult; Apoptosis; Biomarkers; Case-control studies; Child; Female; Genetic predisposition to disease; Humans; Infant; Keratinocytes; Male; Middle aged; Mutant proteins; Mutation; Necrosis; Stevens-johnson syndrome; Young adult; preschool; differentiation; human; t-lymphocyte; Gnly protein; Antigens; Child
• License: Abierto (Texto Completo)