Department of Clinical Genetics and GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
NIHR Southampton Clinical Research Facility and NIHR Southampton Biomedical Research Centre, University of Southampton Faculty of Medicine and University Hospital Southampton, NHS Foundation Trust, Southampton, UK.
Hum Mutat. 2020 Jan;41(1):196-202. doi: 10.1002/humu.23909. Epub 2019 Sep 23.
Idiopathic intestinal varicosis is a developmental disorder defined by dilated and convoluted submucosal veins in the colon or small bowel. A limited number of families with idiopathic intestinal varices has been reported, but the genetic cause has not yet been identified. We performed whole-exome and targeted Sanger sequencing of candidate genes in five intestinal varicosis families. In four families, mutations in the RPSA gene were found, a gene previously linked to congenital asplenia. Individuals in these pedigrees had intestinal varicose veins and angiodysplasia, often in combination with asplenia. In a further four-generation pedigree that only showed intestinal varicosities, the RPSA gene was normal. Instead, a nonsense mutation in the homeobox gene NKX2-3 was detected which cosegregated with the disease in this large family with a LOD (logarithm of the odds) score of 3.3. NKX2-3 is a component of a molecular pathway underlying spleen and gut vasculature development in mice. Our results provide a molecular basis for familial idiopathic intestinal varices. We provide evidence for a relationship between the molecular pathways underlying the development of the spleen and intestinal mucosal vasculature that is conserved between humans and mice. We propose that clinical management of intestinal varices, should include assessment of a functional spleen.
特发性肠静脉曲张是一种以结肠或小肠黏膜下扩张和迂曲静脉为特征的发育性疾病。已经报道了少数特发性肠静脉曲张的家族病例，但遗传原因尚未确定。我们对 5 个肠静脉曲张家系的候选基因进行了全外显子和靶向 Sanger 测序。在 4 个家系中发现了 RPSA 基因突变，该基因先前与先天性无脾症有关。这些家系中的个体存在肠静脉曲张和血管发育不良，常伴有无脾症。在另一个仅显示肠静脉曲张的四代表皮系中，RPSA 基因正常。相反，在这个具有大系谱的家系中检测到同源盒基因 NKX2-3 的无义突变，该突变与疾病共分离，LOD（优势对数）评分为 3.3。NKX2-3 是小鼠脾脏和肠道血管发育的分子途径的组成部分。我们的结果为家族性特发性肠静脉曲张提供了分子基础。我们提供了证据表明，在人类和小鼠之间，脾和肠黏膜血管发育的分子途径之间存在关系。我们建议，肠静脉曲张的临床治疗应包括对功能性脾脏的评估。
