Novel Compound Heterozygous Mutations in HOIP Result in Autoinflammation and Immunodeficiency.

Objective: Mutations in the HOIP gene, encoding Heme-oxidized IRP2 ubiquitin ligase-1 (HOIL-1) interacting protein, a key component of the linear ubiquitination chain assembly complex (LUBAC), affect the activation of the NF-κB pathway and result in autoinflammation and immunodeficiency. To date, only three patients with HOIP mutations have been reported in the English literature. This study aimed to identify the genetic cause in a 1-year-6-month-old boy with early-onset autoinflammation and immunodeficiency.

Methods: Clinical manifestations and immunological phenotypes were assessed in a Chinese patient with novel compound heterozygous mutations in HOIP. Swiss-PdbViewer was used to predict the pathogenicity of the mutations. HOIP and LUBAC protein levels were evaluated by western blot. Immunological phenotypes and intracellular NF-κB phosphorylation in T and B cells were analyzed by flow cytometry, and the interferon (IFN) signature was assessed using quantitative reverse transcription PCR (RT-qPCR).

Results: The patient experienced recurrent fever, multiple site infections, and chronic diarrhea from the neonatal period, requiring repeated hospitalizations. Targeted gene sequencing identified novel compound heterozygous mutations in HOIP (c.1654 C > T, p.Gln552Ter; c.3038 A > C, p.His1013Pro). These mutations significantly reduced HOIP and LUBAC protein expression and altered the HOIP protein structure. Immunophenotyping revealed a reduction in CD8 + T cells, central memory (CD8 CM) and effector memory (CD8 EM) T cells, and CD4 + T cells. Subset analysis of CD4 + T cells showed decreased T follicular helper cells (Tfh) and increased IL-17-producing T helper (Th17) cells. The patient also exhibited a higher percentage of naïve B cells and a lower percentage of memory B cells, alongside impaired NF-κB phosphorylation in T and B cells upon LPS stimulation. The expression of the patient's interferon-stimulated gene (ISG) was markedly higher than that of healthy controls.

Conclusion: HOIP mutations may lead to multiple immune abnormalities, impaired NF-κB activation, and activation of the type I interferon pathway. These findings highlight the diversity of HOIP mutations and expand the clinical spectrum of associated diseases.