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

Dora Janeth Fonseca Mendoza, Luz Adriana Caro, Diana Carolina Sierra Díaz, Carlos Serrano Reyes, Yohjana Carolina Suárez, Heidi Eliana Mateus Arbelaez, David Bolívar Salazar, Ligia Alejandra De la Torre Cifuentes, Paul Laissue Hormaza

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.
Original languageEnglish
JournalHuman Genetics
StatePublished - Oct 14 2019

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