Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Hum Mol Genet. 2023 Jul 4;32(14):2335-2346. doi: 10.1093/hmg/ddad065.
FOXJ1 is expressed in ciliated cells of the airways, testis, oviduct, central nervous system and the embryonic left-right organizer. Ablation or targeted mutation of Foxj1 in mice, zebrafish and frogs results in loss of ciliary motility and/or reduced length and number of motile cilia, affecting the establishment of the left-right axis. In humans, heterozygous pathogenic variants in FOXJ1 cause ciliopathy leading to situs inversus, obstructive hydrocephalus and chronic airway disease. Here, we report a novel truncating FOXJ1 variant (c.784_799dup; p.Glu267Glyfs12) identified by clinical exome sequencing from a patient with isolated congenital heart defects (CHD) which included atrial and ventricular septal defects, double outlet right ventricle (DORV) and transposition of the great arteries. Functional experiments show that FOXJ1 c.784_799dup; p.Glu267Glyfs12, unlike FOXJ1, fails to induce ectopic cilia in frog epidermis in vivo or to activate the ADGB promoter, a downstream target of FOXJ1 in cilia, in transactivation assays in vitro. Variant analysis of patients with heterotaxy or heterotaxy-related CHD indicates that pathogenic variants in FOXJ1 are an infrequent cause of heterotaxy. Finally, we characterize embryonic-stage CHD in Foxj1 loss-of-function mice, demonstrating randomized heart looping. Abnormal heart looping includes reversed looping (dextrocardia), ventral looping and no looping/single ventricle hearts. Complex CHDs revealed by histological analysis include atrioventricular septal defects, DORV, single ventricle defects as well as abnormal position of the great arteries. These results indicate that pathogenic variants in FOXJ1 can cause isolated CHD.
FOXJ1 在气道、睾丸、输卵管、中枢神经系统和胚胎左右组织者中的纤毛细胞中表达。在小鼠、斑马鱼和青蛙中，Foxj1 的缺失或靶向突变导致纤毛运动丧失和/或运动纤毛的长度和数量减少，从而影响左右轴的建立。在人类中，FOXJ1 的杂合致病性变异导致纤毛病，导致 situs inversus、梗阻性脑积水和慢性气道疾病。在这里，我们报告了一种新型截断 FOXJ1 变体（c.784_799dup;p.Glu267Glyfs12），该变体是通过对一名患有孤立性先天性心脏病（CHD）的患者进行临床外显子组测序发现的，该患者包括房间隔和室间隔缺损、右心室双出口（DORV）和大动脉转位。功能实验表明，与 FOXJ1 不同，FOXJ1 c.784_799dup;p.Glu267Glyfs12 无法在体内诱导青蛙表皮中的异位纤毛，也无法在体外的转激活测定中激活 FOXJ1 在纤毛中的下游靶标 ADGB 启动子。对具有异位或异位相关 CHD 的患者进行变体分析表明，FOXJ1 中的致病性变体是异位的罕见原因。最后，我们对 Foxj1 功能丧失型小鼠的胚胎期 CHD 进行了特征描述，证明了心脏环的随机化。异常心脏环包括反向环（右位心）、腹侧环和无环/单心室心脏。组织学分析显示的复杂 CHD 包括房室间隔缺损、DORV、单心室缺陷以及大动脉异常位置。这些结果表明，FOXJ1 中的致病性变体可导致孤立性 CHD。
