Mutations in IL36RN are associated with geographic tongue

Abstract

Geographic tongue (GT) is a benign inflammatory disorder of unknown etiology. Epidemiology and histopathology in previous studies found that generalized pustular psoriasis (GPP) is a factor associated with GT, but the molecular mechanism remains obscure. To investigate the mechanism of GT, with and without GPP, three cohorts were recruited to conduct genotyping of IL36RN, which is the causative gene of GPP. In a family spanning three generations and diagnosed with only GT (“GT alone”), GT was caused by the c.115+6T>C/p.Arg10ArgfsX1 mutation in the IL36RN gene. An autosomal dominant inheritance pattern with incomplete penetrance was observed. In the cohort consisting of sporadic cases of “GT alone” (n = 48), significant associations between GT and three IL36RN variants (c.115+6T>C/p.Arg10ArgfsX1, c.169G>A/p.Val57Ile and c.29G>A/p.Arg10Gln) were shown. In the GPP patient cohort (n = 56) and GPP family member cohort (n = 67), a significant association between the c.115+6T>C mutation and the simultaneous presence of GPP and GT was observed when compared to the presence of GPP without GT (P < 0.05). Biopsies revealed similarities among GT patients with different genotypes (AA, Aa and aa), with the neutrophils prominently infiltrating the epidermis. Western-blot analysis showed that the expression ratio of IL-36Ra/IL-36γ in lesioned tongues with individuals harboring different genotypes (AA, Aa and aa, n = 3, respectively) decreased significantly compared to controls (n = 3). We describe the mechanism of GT for the first time: some cases of GT are caused by IL36RN mutations, while those lacking mutations are associated with an imbalance in expression between IL-36Ra and IL-36γ proteins in tongue tissue.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-016-1750-y) contains supplementary material, which is available to authorized users.

Regulation and function of interleukin‐36 cytokines

“…Finally in a few examined cases of GT with or without IL-36RN mutation, the IL-36Ra/ IL-36γ ratio was decreased in lesioned tongues, suggesting an imbalance between antagonist and agonists in GT. 61 The relationship between IL36RN mutations, protein expression,…”

“…Sporadic cases of GT were also significantly associated with IL36RN variants. Finally in a few examined cases of GT with or without IL‐36RN mutation, the IL‐36Ra/ IL‐36γ ratio was decreased in lesioned tongues, suggesting an imbalance between antagonist and agonists in GT …”

Association between geographic tongue and psoriasis: A systematic review and meta‐analyses

“…The statistically significant presence of human leucocyte antigen HLA‐Cw6 and B13 has been observed in patients with psoriasis vulgaris and in patients with GT when compared with a control group . More recently it has been determined that both patients with generalised pustular psoriasis and patients with GT exhibit the c.115 + 6T>C mutation in the IL36RN gene …”

Coinheritance of generalized pustular psoriasis and familial Behçet‐like autoinflammatory syndrome with variants in IL36RN and TNFAIP3 in the heterozygous state

“…14 In our case, whether the variant of TNFAIP3 plays a part in the development of GPP, or TNFAIP3 simply causes the Behc ßet's disease phenotype, still remains unknown. In our opinion, TNFAIP3 is more likely to act as a modifier allele in GPP, because the clinical manifestations of a single heterozygous variant of c.115+6T>C in IL36RN ranged from unaffected, 6 GT alone, 13 mild localized pustular psoriasis to severe systemic GPP. [4][5][6][7] The proband with coexistent variants of TNFAIP3 and IL36RN manifested severe GPP, but his heterozygous father with an IL36RN variant alone was normal.…”

“…Some pedigree analyses are more informative. We previously reported on a family whose male homozygous proband with c.115+6T>C was affected by severe GPP (with GT), while his three female homozygous sisters, his mother and the sister with a single heterozygous mutation were all affected with “GT alone” (without GPP). His heterozygous father was normal (without GPP or GT).…”