Abstract
Most humans are exposed to Tropheryma whipplei (Tw). Whipple's disease (WD) strikes only a small minority of individuals infected with Tw (<0.01%), whereas asymptomatic chronic carriage is more common (<25%). We studied a multiplex kindred, containing four WD patients and five healthy Tw chronic carriers. We hypothesized that WD displays autosomal dominant (AD) inheritance, with age-dependent incomplete penetrance. We identified a single very rare non-synonymous mutation in the four patients: the private R98W variant of IRF4, a transcription factor involved in immunity. The five Tw carriers were younger, and also heterozygous for R98W. We found that R98W was loss-of-function, modified the transcriptome of heterozygous leukocytes following Tw stimulation, and was not dominant-negative. We also found that only six of the other 153 known non-synonymous IRF4 variants were loss-of-function. Finally, we found that IRF4 had evolved under purifying selection. AD IRF4 deficiency can underlie WD by haploinsufficiency, with age-dependent incomplete penetrance.
Highlights
Whipple’s disease (WD) was first described as an intestinal inflammatory disease by George H
We investigated four related patients diagnosed with WD (P1, P2, P3, and P4) with a mean age at diagnosis of 58 years
The IRF4 gene has a gene damage index (GDI) of 2.85, a neutrality index score of 0.15 (Itan et al, 2015), and a purifying selection f parameter of 0.32, strongly suggesting that IRF4 has evolved under purifying selection (Eilertson et al, 2012)
Summary
Whipple’s disease (WD) was first described as an intestinal inflammatory disease by George H. University in Baltimore – described a new inflammatory disease that affects the intestine Patients with this condition, known as Whipple’s disease, experience diarrhea, weight loss, and abdominal and joint pain. From the 1950s onwards, scientists identified a few families with multiple members who have developed Whipple’s disease These observations suggested that human genes may play a role in determining whether a person infected with T. whipplei becomes ill. Guérin et al report that, in one French family, an extremely rare mutation in the gene that codes for a protein called IRF4 may contribute to the development of Whipple’s disease. Guérin et al suggest that Whipple’s disease may be caused by specific genetic mutations affecting the immune system in subjects infected by T. whipplei.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
