Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France.
Imagine Institute, Paris Descartes University, Paris, France.
Elife. 2018 Mar 14;7:e32340. doi: 10.7554/eLife.32340.
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.
大多数人都接触过（Tw）。惠尔氏病（WD）仅侵袭一小部分感染 Tw 的个体（<0.01%），而无症状慢性携带更为常见（<25%）。我们研究了一个多重家族，其中包含四名 WD 患者和五名健康的 Tw 慢性携带者。我们假设 WD 表现出常染色体显性（AD）遗传，具有年龄依赖性不完全外显率。我们在四名患者中发现了一个单一的非常罕见的非同义突变：IRF4 的私有 R98W 变体，这是一种参与免疫的转录因子。这五个 Tw 携带者年龄较小，且也为 R98W 杂合子。我们发现 R98W 是失活功能的，它改变了 Tw 刺激后异质白细胞的转录组，并且不是显性负性的。我们还发现，在其他 153 个已知的非 synonymous IRF4 变体中，只有 6 个是失活功能的。最后，我们发现 在净化选择下进化。AD IRF4 缺陷可通过杂合子不足引起 WD，具有年龄依赖性不完全外显率。
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