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Mutant GNLY is linked to Stevens–Johnson syndrome and toxic epidermal necrolysis
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Fonseca Mendoza, Dora Janeth
Caro L.A.
Sierra-Díaz D.C.
Serrano-Reyes C.
Londoño O.
Suárez Y.C.
Mateus H.E.
Bolívar-Salazar D.
Ramírez A.F.
de-la-Torre, Alejandra
Fecha
2019
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Springer
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Resumen
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. © 2019, Springer-Verlag GmbH Germany, part of Springer Nature.
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Carbamazepine , preschool , differentiation , Cefalexin , human , Cocodamol , t-lymphocyte , Contrast medium , Cotrimoxazole , Granulysin , Lamotrigine , Metoclopramide , Phenytoin , Pyrimethamine plus sulfadoxine , Sulfonamide , Biological marker , Gnly protein , 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 , Antigens , Apoptosis , Biomarkers , Case-control studies , Child , Child , Female , Genetic predisposition to disease , Humans , Infant , Keratinocytes , Male , Middle aged , Mutant proteins , Mutation , Necrosis , Stevens-johnson syndrome , Young adult
