Novel Compound Heterozygous Mutations in HOIP Result in Autoinflammation and Immunodeficiency

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Mutations in the HOIP gene, encoding a key component of the linear ubiquitination chain assembly complex (LUBAC), are linked to autoinflammation and immunodeficiency.
• HOIP mutations impact NF-κB pathway activation.
• Only three cases of HOIP mutations have been previously reported.

Purpose of the Study:

• To identify the genetic cause of early-onset autoinflammation and immunodeficiency in a pediatric patient.
• To characterize the immunological phenotype associated with novel HOIP mutations.

Main Methods:

• Clinical and immunological assessments of a Chinese patient with compound heterozygous HOIP mutations.
• Genetic sequencing to identify mutations.
• Western blot to evaluate protein levels.
• Flow cytometry for immunophenotyping and NF-κB phosphorylation analysis.
• RT-qPCR to assess interferon signature.

Main Results:

• A novel compound heterozygous mutation in HOIP was identified, leading to reduced HOIP and LUBAC protein expression.
• Significant alterations in T and B cell populations were observed, including decreased CD8+ T cells, Tfh cells, and memory B cells, with increased Th17 cells.
• Impaired NF-κB phosphorylation and elevated interferon-stimulated gene (ISG) expression were noted.

Conclusions:

• HOIP mutations can cause diverse immune abnormalities, including impaired NF-κB activation and type I interferon pathway activation.
• These findings broaden the understanding of HOIP-related diseases and highlight the mutational diversity.
• The study expands the clinical spectrum of autoinflammatory and immunodeficiency disorders linked to HOIP.