OTULIN and Infantile‑Onset Periodic Fever‑Panniculitis‑Dermatosis Syndrome

OTULIN (HGNC:25118) encodes a linear deubiquitinase that plays a critical role in regulating inflammatory signaling via removal of M1‐linked ubiquitin chains. Biallelic loss‑of‑function mutations in OTULIN are primarily implicated in the rare autoinflammatory disorder infantile‑onset periodic fever‑panniculitis‑dermatosis syndrome (MONDO_0014912), also known as ORAS or Otulipenia. Several independent reports, including both case studies and multi‑patient investigations, have implicated diverse mutational mechanisms such as homozygous and compound heterozygous missense variants in establishing a clear genotype‑phenotype correlation (PMID:32721894, PMID:35170849).

Genetic evidence supports an autosomal recessive mode of inheritance in the majority of cases. Multiple families have been reported with pathogenic variants segregating with the disease, and a variety of variant classes have been identified. For instance, the recurrent variant c.815T>C (p.Leu272Pro) was observed in a patient’s iPS cells, consistent with loss‑of‑function effects (PMID:32721894). Additional familial studies have identified compound heterozygous as well as homozygous mutations, further strengthening the link between OTULIN dysfunction and the autoinflammatory phenotype. Although one report described a de novo dominant‑negative mutation, the collective genetic data overwhelmingly supports a recessive model.

Functional and experimental studies complement the genetic data by demonstrating that OTULIN deficiency disrupts linear ubiquitin homeostasis and TNF‑induced signaling. In vitro assays, murine models, and analyses of patient‑derived cells have all shown impaired deubiquitinase activity, reduced protein stability, and abnormal accumulation of linear ubiquitin chains, which together promote inflammatory cell death and dysregulated cytokine release (PMID:30804083, PMID:38000038). Such functional concordance is critical for translating molecular findings into diagnostic and therapeutic approaches.

Despite the robust evidence supporting an autosomal recessive inheritance for ORAS, there exists a limited body of literature reporting dominant‑negative effects in select cases. These studies suggest that additional mutational mechanisms may modify the clinical spectrum of OTULIN‑related disease; however, the primary genetic architecture remains characterized by recessive loss‑of‑function alleles. This complexity underscores the necessity for thorough genetic screening and detailed phenotypic assessment in suspected cases.

Integration of the genetic and functional data reveals a strong association between OTULIN variants and infantile‑onset periodic fever‑panniculitis‑dermatosis syndrome. The evidence from multiple independent studies—spanning case reports, family segregations, and experimental assays—demonstrates the clinical utility of OTULIN testing for diagnosis and management of this autoinflammatory syndrome. Clinicians and commercial diagnostic laboratories may confidently incorporate OTULIN genetic screening into their panels to facilitate early diagnosis and guide therapeutic decision‑making.

Key Take‑Home: Robust genetic and functional evidence affirm OTULIN as a critical gene in the pathogenesis of infantile‑onset periodic fever‑panniculitis‑dermatosis syndrome, supporting its use in diagnostic and prognostic applications.

References

• Stem cell research • 2020 • Human induced pluripotent stem cells generated from a patient with a homozygous L272P mutation in the OTULIN gene PMID:32721894
• EMBO molecular medicine • 2022 • Compound heterozygous variants in OTULIN are associated with fulminant atypical late‑onset ORAS PMID:35170849
• The Journal of experimental medicine • 2024 • A de novo dominant‑negative variant is associated with OTULIN‑related autoinflammatory syndrome PMID:38652464
• Research square • 2024 • OTULIN‑related conditions: Report of a new case and review of the literature using GenIA PMID:38712244
• Clinical immunology • 2024 • OTULIN‑related conditions: Report of a new case and review of the literature using GenIA PMID:38914362
• EMBO molecular medicine • 2019 • OTULIN deficiency in ORAS causes cell type‑specific LUBAC degradation, dysregulated TNF signalling and cell death PMID:30804083
• Molecular biology reports • 2022 • Screening of OTULIN gene mutation with targeted next generation sequencing in Turkish populations and in silico analysis of these mutations PMID:35294702
• Science immunology • 2023 • Myeloid OTULIN deficiency couples RIPK3‑dependent cell death to Nlrp3 inflammasome activation and IL‑1β secretion PMID:38000038
• The Journal of experimental medicine • 2024 • Dominant negative OTULIN‑related autoinflammatory syndrome PMID:38630025

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