IRF4 haploinsufficiency in a multiplex family with Whipple's disease

Area of Science:

• Genetics
• Immunology
• Infectious Diseases

Background:

• Tropheryma whipplei (T. whipplei) bacteria cause Whipple's disease (WD), but only a small fraction of infected individuals develop the condition.
• The genetic basis for WD susceptibility in T. whipplei-infected individuals remains largely unknown.
• Previous studies suggested a role for IRF4 gene variants in a large family with WD.

Purpose of the Study:

• To investigate the genetic cause of Whipple's disease in two unrelated family members.
• To characterize the functional impact of a specific IRF4 gene variant.
• To determine if IRF4 haploinsufficiency contributes to WD in additional families.

Main Methods:

• Whole-exome sequencing was performed on affected mother and son.
• Biochemical assays characterized the DNA binding and transcriptional activity of the identified IRF4 variant.
• Immunological analysis of patient leukocytes assessed immune function.

Main Results:

• Both patients were heterozygous for a rare hypomorphic IRF4 missense variant (p.R25S).
• This variant impaired IRF4 DNA binding and transcription induction but did not exhibit negative dominance.
• Immune function was otherwise normal in the patients, supporting IRF4 haploinsufficiency as the cause.

Conclusions:

• Haploinsufficiency of the IRF4 gene can cause Whipple's disease in Tropheryma whipplei-infected individuals.
• This genetic susceptibility is present in at least two unrelated families.
• The findings highlight the importance of genetic factors in determining WD development.