Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children's Hospital, and Harvard Medical School, Boston, MA, 02115, USA.
Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
J Crohns Colitis. 2021 Nov 8;15(11):1908-1919. doi: 10.1093/ecco-jcc/jjab077.
Very early onset inflammatory bowel disease [VEOIBD] is characterized by intestinal inflammation affecting infants and children less than 6 years of age. To date, over 60 monogenic aetiologies of VEOIBD have been identified, many characterized by highly penetrant recessive or dominant variants in underlying immune and/or epithelial pathways. We sought to identify the genetic cause of VEOIBD in a subset of patients with a unique clinical presentation.
Whole exome sequencing was performed on five families with ten patients who presented with a similar constellation of symptoms including medically refractory infantile-onset IBD, bilateral sensorineural hearing loss and, in the majority, recurrent infections. Genetic aetiologies of VEOIBD were assessed and Sanger sequencing was performed to confirm novel genetic findings. Western analysis on peripheral blood mononuclear cells and functional studies with epithelial cell lines were employed.
In each of the ten patients, we identified damaging heterozygous or biallelic variants in the Syntaxin-Binding Protein 3 gene [STXBP3], a protein known to regulate intracellular vesicular trafficking in the syntaxin-binding protein family of molecules, but not associated to date with either VEOIBD or sensorineural hearing loss. These mutations interfere with either intron splicing or protein stability and lead to reduced STXBP3 protein expression. Knock-down of STXBP3 in CaCo2 cells resulted in defects in cell polarity.
Overall, we describe a novel genetic syndrome and identify a critical role for STXBP3 in VEOIBD, sensorineural hearing loss and immune dysregulation.
非常早发性炎症性肠病[VEOIBD]的特征是影响 6 岁以下婴儿和儿童的肠道炎症。迄今为止，已经确定了 60 多种 VEOIBD 的单基因病因，其中许多是由潜在免疫和/或上皮途径中的高穿透性隐性或显性变异引起的。我们试图在具有独特临床表现的一组患者中确定 VEOIBD 的遗传原因。
对五个家系的十名患者进行全外显子组测序，这些患者具有相似的症状组合，包括医学难治性婴儿期 IBD、双侧感觉神经性听力损失，且大多数患者存在复发性感染。评估 VEOIBD 的遗传病因，并进行 Sanger 测序以确认新的遗传发现。对外周血单核细胞进行 Western 分析，并对上皮细胞系进行功能研究。
在这 10 名患者中的每一名患者中，我们均发现了Syntaxin-Binding Protein 3 基因[STXBP3]的有害杂合或纯合变异，该基因编码一种已知可调节细胞内囊泡运输的蛋白，属于Syntaxin-binding protein 家族的分子，但迄今为止与 VEOIBD 或感觉神经性听力损失无关。这些突变干扰了内含子剪接或蛋白稳定性，导致 STXBP3 蛋白表达减少。在 CaCo2 细胞中敲低 STXBP3 会导致细胞极性缺陷。
总的来说，我们描述了一种新的遗传综合征，并确定了 STXBP3 在 VEOIBD、感觉神经性听力损失和免疫失调中的关键作用。
