IRF4 haploinsufficiency in a family with Whipple's disease.

Elife 2018 03 14;7. Epub 2018 Mar 14.

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.

Most humans are exposed to (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 had evolved under purifying selection. AD IRF4 deficiency can underlie WD by haploinsufficiency, with age-dependent incomplete penetrance.

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http://dx.doi.org/10.7554/eLife.32340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915175PMC
March 2018

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