RESUMEN
The vertebrate left-right axis is specified during embryogenesis by a transient organ: the left-right organizer (LRO). Species including fish, amphibians, rodents and humans deploy motile cilia in the LRO to break bilateral symmetry, while reptiles, birds, even-toed mammals and cetaceans are believed to have LROs without motile cilia. We searched for genes whose loss during vertebrate evolution follows this pattern and identified five genes encoding extracellular proteins, including a putative protease with hitherto unknown functions that we named ciliated left-right organizer metallopeptide (CIROP). Here, we show that CIROP is specifically expressed in ciliated LROs. In zebrafish and Xenopus, CIROP is required solely on the left side, downstream of the leftward flow, but upstream of DAND5, the first asymmetrically expressed gene. We further ascertained 21 human patients with loss-of-function CIROP mutations presenting with recessive situs anomalies. Our findings posit the existence of an ancestral genetic module that has twice disappeared during vertebrate evolution but remains essential for distinguishing left from right in humans.
Asunto(s)
Evolución Biológica , Tipificación del Cuerpo , Redes Reguladoras de Genes , Metaloproteasas , Animales , Humanos , Tipificación del Cuerpo/genética , Tipificación del Cuerpo/fisiología , Cilios/genética , Mutación con Pérdida de Función , Metaloproteasas/genética , Metaloproteasas/fisiología , Proteínas/genética , Proteínas/fisiología , Vertebrados/genéticaRESUMEN
As thromboembolic events (TEE) are common in adults with congenital heart disease (ACHD), adequate oral anticoagulation for prophylaxis or treatment of TEE is important. Until now, mainly vitamin K antagonists have been used in these patients. The purpose of this study was to provide first data on the use of direct oral anticoagulants in ACHD. This prospective, observational, and longitudinal study included 102 consecutive ACHD, of whom 75 (37 women and 38 men; mean age 50 ± 13 years) could be analyzed. Most common CHD were pre-tricuspid shunts (n = 31; 41%), complex CHD (n = 16; 21%), left heart/aortic valve anomalies (n = 5; 6%), right-sided cardiac/pulmonary artery anomalies (n = 9; 13%), post-tricuspid shunts (n = 3; 4%), and others (n = 11; 15%). Five patients had cyanosis and 3 patients a Fontan circulation. Mean follow-up was 12 ± 11 months. Rivaroxaban was administered in 55 patients, apixaban in 13 and dabigatran in 7 patients for TEE prophylaxis in atrial arrhythmias (n = 57), stroke/transient ischemic attacks (n = 11), deep vein thrombosis (n = 4), pulmonary embolism (n = 1) and atrial thrombi (n = 3). Some patients had >1 indication for adequate oral anticoagulation. CHA2-DS2-VASc score was ≥ 2 in 23 (31%), and 9 (12%) had a HAS-BLED score ≥ 2. There were neither thrombotic or major bleeding events nor major side effects. In conclusion, direct oral anticoagulants appear to be safe and effective in ACHD. Long-term follow-up is needed to substantiate these findings.
Asunto(s)
Anticoagulantes/administración & dosificación , Cardiopatías Congénitas/complicaciones , Tromboembolia/prevención & control , Administración Oral , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Tromboembolia/etiología , Resultado del Tratamiento , Adulto JovenRESUMEN
Heterotaxy results from a failure to establish normal left-right asymmetry early in embryonic development. By whole-exome sequencing, whole-genome sequencing and high-throughput cohort resequencing, we identified recessive mutations in MMP21 (encoding matrix metallopeptidase 21) in nine index cases with heterotaxy. In addition, Mmp21-mutant mice and mmp21-morphant zebrafish displayed heterotaxy and abnormal cardiac looping, respectively, suggesting a new role for extracellular matrix remodeling in the establishment of laterality in vertebrates.