IL36RN Mutations Affect Protein Expression and Function: A Basis for Genotype-Phenotype Correlation in Pustular...

Area of Science:

• Genetics and Molecular Biology
• Immunodermatology
• Human Genetics

Background:

• Mutations in the IL36RN gene, encoding the IL-36 receptor antagonist (IL-36Ra), are linked to pustular psoriasis.
• Understanding the specific impact of different IL36RN mutations is crucial for diagnosing and managing these inflammatory skin conditions.

Purpose of the Study:

• To identify and characterize novel IL36RN mutations in patients with familial generalized pustular psoriasis.
• To investigate the functional consequences of various IL36RN mutations on IL-36Ra protein expression and activity.
• To establish genotype-phenotype correlations in patients with deficiency of the IL-36Ra (DITRA).

Main Methods:

• Identification of homozygous IL36RN mutations in familial generalized pustular psoriasis patients.
• Site-directed mutagenesis and HEK293T cell expression to analyze IL-36Ra protein levels.
• Functional assays to assess the impact of mutations on IL-36-mediated NF-κB pathway activation.

Main Results:

• Two novel homozygous IL36RN mutations (c.41C>A/p.Ser14X and c.420_426del/p.Gly141MetfsX29) were identified.
• Mutations were classified as null (complete absence of functional IL-36Ra) or hypomorphic (decreased or unchanged expression/function).
• Null mutations correlated with severe phenotypes (generalized pustular psoriasis, acute generalized exanthematous pustular eruption), while hypomorphic mutations were associated with localized or generalized variants.

Conclusions:

• IL36RN mutations differentially impact IL-36Ra function, leading to distinct pustular psoriasis phenotypes.
• This study provides a foundation for genotype-phenotype correlations in DITRA.
• Additional factors likely modulate the clinical expression of IL36RN-associated autoinflammatory disorders.