A novel TRAF3IP2 variant causing familial scarring alopecia with mixed features of discoid lupus erythematosus and folliculitis decalvans
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Blackwell Publishing Ltd
Abstract
Discoid lupus erythematosus (DLE) is an autoimmune disorder with a poorly defined etiology. Despite epidemiologic gender and ethnic biases, a clear genetic basis for DLE remains elusive. In this study, we used exome and RNA sequencing technologies to characterize a consanguineous Lebanese family with four affected individuals who presented with classical scalp DLE and generalized folliculitis. Our results unraveled a novel biallelic variant c.1313C > A leading to a missense substitution p.(Thr438Asn) in TRAF3IP2(NM_147200.3). Expression studies in cultured cells revealed mis-localization of the mutated protein. Functional characterization of the mutated protein showed significant reduction in the physical interaction with the interleukin 17-A receptor (IL17RA), while interaction with TRAF6 was unaffected. By conducting a differential genome-wide transcriptomics analysis between affected and non-affected individuals, we showed that the hair follicle differentiation pathway is drastically suppressed, whereas cytokine and inflammation responses are significantly upregulated. Furthermore, our results were highly concordant with molecular signatures in patients with DLE from a public dataset. In conclusion, this is the first report on a new putative role for TRAF3IP2 in the etiology of DLE. The identified molecular features associated with this gene could pave the way for better DLE-targeted treatment. © 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
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Alopecia, Lupus, Scarring, Skin, Traf3ip2, Adaptor proteins, signal transducing, Adolescent, Child, Child, preschool, Consanguinity, Female, Folliculitis, Genetic predisposition to disease, Humans, Intracellular signaling peptides and proteins, Lupus erythematosus, discoid, Male, Pedigree, Protein binding, Protein interaction maps, Receptors, interleukin-17, Sequence analysis, rna, Whole exome sequencing, Antibiotic agent, Asparagine, Cytokine, Doxycycline, Interleukin 17 receptor, Interleukin 17a receptor, Mutant protein, Rna, Steroid, Threonine, Traf31p2 protein, Tumor necrosis factor receptor associated factor, Tumor necrosis factor receptor associated factor 6, Unclassified drug, Il17ra protein, human, Signal peptide, Signal transducing adaptor protein, Tifab protein, human, Traf3ip2 protein, human, Allele, Antibiotic therapy, Article, Case control study, Cell culture, Cell differentiation, Clinical article, Clinical feature, Controlled study, Discoid lupus erythematosus, Epidermis hyperplasia, Familial disease, Family, Gene expression, Genetic variability, Genome-wide association study, Hair follicle, Hek293t cell line, Human, Human cell, Inflammation, Lebanese, Missense mutation, Molecular genetics, Priority journal, Protein localization, Protein protein interaction, Receptor upregulation, Rna sequencing, Scalp, Scar formation, Signal transduction, Skin biopsy, Steroid therapy, Transcriptomics, Diagnostic imaging, Genetic predisposition, Genetics, Pathology, Preschool child, Protein analysis, Sequence analysis