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Mutant GNLY Is Linked to Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis

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Mutant GNLY Is Linked to Stevens–Johnson Syndrome and Toxic Epidermal Necrolysis Human Genetics (2019) 138:1267–1274 https://doi.org/10.1007/s00439-019-02066-w ORIGINAL INVESTIGATION Mutant GNLY is linked to Stevens–Johnson syndrome and toxic epidermal necrolysis Dora Janeth Fonseca1 · Luz Adriana Caro2 · Diana Carolina Sierra‑Díaz1 · Carlos Serrano‑Reyes3 · Olga Londoño1 · Yohjana Carolina Suárez1 · Heidi Eliana Mateus1 · David Bolívar‑Salazar1 · Ana Francisca Ramírez4 · Alejandra de‑la‑Torre5 · Paul Laissue1 Received: 11 July 2019 / Accepted: 25 September 2019 / Published online: 14 October 2019 © Springer-Verlag GmbH Germany, part of Springer Nature 2019 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 identifed 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 efect. Our results argue in favour of GNLY non-synonymous sequence variants contributing to SJS/TEN pathophysiology, thereby constituting a promising, clinically useful molecular biomarker. Introduction skin detachment secondary to keratinocyte death, and ocular involvement (Duong et al. 2017). Respiratory and gastroin- Stevens–Johnson syndrome (SJS) and toxic epidermal testinal systems can sometimes be afected. SJS and TEN necrolysis (TEN) are rare severe cutaneous adverse reac- are considered to be variations of the same hypersensitiv- tions (SCAR) to drugs characterised by exanthema, erosion ity disorder. Patients are classifed as sufering from SJS of the skin and mucous membranes, purpura, blistering, and TEN when < 10% and > 30% of the total body surface area (TBSA) are afected, respectively (Roujeau 1997). SJS/ TEN overlap has been used for classifying patients sufering Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s0043 9-019-02066 -w) contains 10–30% TBSA injury. supplementary material, which is available to authorized users. All of the disease’s presentations involve high mortal- ity rates, ranging from 1–5% (SJS) to 30–50% (TEN). SJS * Paul Laissue and TEN are rare disorders since they afect ~ 1.5 to 1.9 [email protected] individuals per million inhabitants worldwide per year 1 Center For Research in Genetics and Genomics (CIGGUR), (Harr and French 2010; Letko et al. 2005). At least 200 GENIUROS Research Group, School of Medicine drugs to date have been related to the disease’s onset, such and Health Sciences, Universidad del Rosario, Carrera 24 as allopurinol, nonsteroidal anti-infammatories, antimi- No. 63C-69, Bogotá, DC 112111, Colombia crobial sulpha, antiepileptic and antiretroviral molecules 2 Unidad de Quemados, Hospital Simón Bolívar, Bogotá, (Harr and French 2010). SJS/TEN pathophysiology has not Colombia yet been completely understood, but it has been shown that 3 Unidad de Alergia, Fundación Valle de Lili, Cali, Colombia distinct immune system cells and molecules (e.g. CD8-T 4 Departamento de Dermatología, Fundación Valle de Lili, and NK cells, FasL and granulysin cytolytic proteins) are Cali, Colombia key actors in the disease’s pathogenesis (Schwartz et al. 5 Servicio de Inmunología, Grupo Neuros, Escuela de 2013). Specifc HLA-B alleles’ genetic associations have Medicina y Ciencias de la Salud, Universidad del Rosario, been linked to the phenotype. For instance, it has been Bogotá, Colombia Vol.:(0123456789)1 3 1268 Human Genetics (2019) 138:1267–1274 suggested that the HLA-B*1502 subtype in Asian popu- Our results argue in favour of GNLY non-synonymous lations might be a genetic marker for the disease. Chung sequence variants contributing to SJS/TEN pathophysiology, et al. observed a strong correlation between this allele and thereby constituting a promising, clinically useful molecular SJS/TEN in Han Chinese individuals who were receiving biomarker. carbamazepine (Chung et al. 2004). Subsequent studies involving additional southeastern populations have con- frmed HLA-B*1502 patients’ susceptibility to carba- Materials and methods mazepine and further antiepileptic drugs (Fan et al. 2017; Man et al. 2007; Tassaneeyakul et al. 2010). Allopurinol Patients and controls treatment and HLA-B*5801 have been strongly associated with severe adverse drug reactions in Asian (Han Chinese, The clinical features defined by Roujeau were used for Japanese and Thai) and (to a lesser extent) Caucasians the patients’ diagnostic classifcation (2). Nineteen (SJS-1 populations (Harr and French 2010; Pavlos et al. 2012; through SJS-19) patients were included in the present study: Yip et al. 2015). 5 SJS, 2 SJS/TEN and 12 TEN (Table 1). They attended However, these and other HLA associations with spe- the Hospital Simón Bolívar (Bogotá, Colombia) or the Fun- cifc drug-induced SJS/TEN phenotypes have been limited dación Valle de Lili (Cali, Colombia). Two patients belonged to specifc ethnicities. Furthermore, the exact functional to the same family (a woman SJS-18 and her son SJS-19). mechanism linking HLA polymorphic molecules and T Eleven drugs were associated with the symptoms’ onset: cells’ cytotoxic response has not been completely elucidated. carbamazepine (4 cases), lamotrigine (3), contrast media (2), Polymorphisms in a few other genes have been proposed sulfadoxine/pyrimethamine (2, the familial case), codeine/ as being potentially related to SJS/TEN, such as EPHX1, paracetamol (1), cephalexin (1), sulphonamide (1), phe- CYP2C9, CYP2B6 and IKZFI (Caruso et al. 2014; Ciccacci nytoin (1), trimethoprim/sulfamethoxazole (1), metoclo- et al. 2013; He et al. 2014; Ueta et al. 2015). pramide (2) and Urtica dioica (1) (Table 1). Two groups of Several molecular mediators have been described for individuals (GP1 and GP2), lacking antecedents of adverse SJS/TEN pathophysiology, such as granulysin (GNLY), reactions to drugs, were created to screen the c.11G > A TNF-α, Fas–Fas ligand interaction, TNF-related apoptosis- (p.Trp4Ter) variant. GP1 consisted of 99 Colombian indi- inducing ligand (TRAIL), and perforin–granzyme B (Har- viduals who had taken phenytoin for at least 6 months while ris et al. 2016). GNLY has been shown to play a key role GP2 included 150 healthy women from the Valledupar area in keratinocyte apoptosis since its expression was higher (a northern region of Colombia). than that for other cytotoxic proteins in SJS/TEN-afected The Universidad del Rosario (Code: DVG-098) and Fun- individuals’ blister fuids from skin lesions (Chung et al. dación Valle de Lili’s (Code: P-515) Ethical Committees 2008). Interestingly, GNLY has also been shown to have approved the study. The clinical investigation followed Hel- proinfammatory activator and chemoattractive properties sinki Declaration guidelines (1975, as revised in 1996). All which may contribute towards the SJS/TEN phenotype (Finn patients had signed informed consent forms. et al. 2011). GNLY has been found to be high in SJS/TEN patients’ plasma (before the onset of skin detachment or GNLY sequencing and in silico analysis mucosal lesions) which has enabled it to be used as a poten- tial biomarker for the disease’s early phases (Abe et al. 2009; Genomic DNA was isolated from whole-blood samples from Yang et al. 2017). However, the exact mechanisms underlin- all patients and GP1–GP2 individuals, using the standard ing GNLY overexpression and toxicity contributing to the salting-out procedure. SJS/TEN phenotype are yet to be discovered. The complete GNLY encoding region (5 exons, The present study has hypothesised that GNLY-encod- ENST00000263863) was amplifed by PCR using exon- ing mutations might be related to the protein’s structural/ fanking primers. The amplicons were then purifed and functional disturbances, thereby contributing to SJS/TEN directly sequenced using internal oligonucleotides enabling pathogenesis. We thus sequenced GNLY’s coding region in intron-exon boundaries to be studied. Genetic screening of a group of 19 Colombian SJS/TEN patients. We identifed GP1-GP2 individuals was used for c.11G > A (p.Trp4Ter), the c.11G > A heterozygous sequence variant in a woman by implementing an identical protocol to that used with afected by TEN, which creates a premature termination patients. Primer sequences and PCR conditions are avail- codon (PTC) (p.Trp4Ter). We show that a mutant protein is able upon request. Sequence variants’ minor allele fre- synthesised, possibly due to a PTC-readthrough mechanism. quencies (MAF) were screened in the Genome Aggrega- Functional in vitro assays demonstrated that the mutant pro- tion Database (gnomAD) (gnomad.broadinstitute.org). The tein was abnormally located in the nuclear compartment, c.11G > A (p.Trp4Ter) variant allele frequency identifed potentially leading to a toxic efect. in the patient was compared to that regarding GP1-GP2 1 3 Human Genetics (2019) 138:1267–1274 1269 Table 1 Patients’ clinical characteristics ID Age Gender Drug Symptoms Phenotype Systemic Mucosal involvement Rash/fictenas
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