INSERM, UMR1163, Laboratory of Intestinal Immunity and Institut Imagine, Paris, France.
GENIUS group from ESPGHAN.
EMBO Mol Med. 2018 Apr;10(4). doi: 10.15252/emmm.201708483.
Herein, we report the first identification of biallelic-inherited mutations in as a Mendelian cause of inflammatory bowel disease in two unrelated patients. encodes for intestinal phosphatase alkaline, a brush border metalloenzyme that hydrolyses phosphate from the lipid A moiety of lipopolysaccharides and thereby drastically reduces Toll-like receptor 4 agonist activity. Prediction tools and structural modelling indicate that all mutations affect critical residues or inter-subunit interactions, and heterologous expression in HEK293T cells demonstrated that all mutations were loss of function. mutations impaired either stability or catalytic activity of ALPI and rendered it unable to detoxify lipopolysaccharide-dependent signalling. Furthermore, ALPI expression was reduced in patients' biopsies, and ALPI activity was undetectable in ALPI-deficient patient's stool. Our findings highlight the crucial role of ALPI in regulating host-microbiota interactions and restraining host inflammatory responses. These results indicate that mutations should be included in screening for monogenic causes of inflammatory bowel diseases and lay the groundwork for ALPI-based treatments in intestinal inflammatory disorders.
在此，我们报道了在两个无关联的患者中，碱性磷酸酶 1（ALPI）的双等位基因遗传突变是炎症性肠病（IBD）的孟德尔病因。ALPI 编码肠道碱性磷酸酶，是一种刷状缘金属酶，可从脂多糖的脂质 A 部分水解磷酸，从而大大降低 Toll 样受体 4 激动剂的活性。预测工具和结构建模表明，所有突变均影响关键残基或亚基间相互作用，并且在 HEK293T 细胞中的异源表达表明所有 ALPI 突变均为功能丧失突变。ALPI 突变破坏了 ALPI 的稳定性或催化活性，使其无法解毒脂多糖依赖性信号转导。此外，患者活检中 ALPI 的表达减少，ALPI 缺乏症患者粪便中无法检测到 ALPI 活性。我们的研究结果强调了 ALPI 在调节宿主-微生物相互作用和抑制宿主炎症反应中的关键作用。这些结果表明，应将 ALPI 突变纳入炎症性肠病单基因病因的筛查中，并为基于 ALPI 的肠道炎症性疾病治疗奠定基础。
