Novel loss-of-function intronic mutation in ELF4 is associated with intestinal autoinflammation

Area of Science:

• Genetics
• Immunology
• Gastroenterology

Background:

• Monogenic errors of immunity can manifest as inflammatory bowel disease (IBD)-like enteropathy.
• Understanding genetic underpinnings of IBD and autoinflammatory conditions is crucial for diagnosis and treatment.

Purpose of the Study:

• To identify the genetic cause of an IBD- and Behçet's-like phenotype in an adolescent.
• To elucidate the functional consequences of a novel mutation in the ELF4 gene.

Main Methods:

• Genetic sequencing to identify mutations.
• Analysis of mRNA and protein expression levels.
• Functional assays to assess transcriptional activity and cytokine secretion.
• Single-cell transcriptional profiling of colonic biopsies.

Main Results:

• A loss-of-function intronic mutation (c.248-7G>A) in the X-linked ELF4 gene was identified.
• The mutation leads to abnormal splicing, reduced ELF4 mRNA and protein expression, and impaired transcriptional activity.
• Patient's cells exhibit autoinflammatory responses, including increased interleukin-6 secretion.
• Single-cell profiling revealed immune dysregulation in the colon, with signatures resembling Crohn's disease, heightened angiogenesis, and enhanced innate immune cell chemotaxis.

Conclusions:

• A novel ELF4 loss-of-function mutation predisposes to an intestinal autoinflammatory disorder.
• This finding expands the spectrum of monogenic causes of IBD-like conditions.
• ELF4 plays a critical role in regulating immune homeostasis and preventing autoinflammation.